BR112015006726B1 - COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND OR A PHARMACEUTICAL COMPOSITION - Google Patents
COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND OR A PHARMACEUTICAL COMPOSITION Download PDFInfo
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- BR112015006726B1 BR112015006726B1 BR112015006726-3A BR112015006726A BR112015006726B1 BR 112015006726 B1 BR112015006726 B1 BR 112015006726B1 BR 112015006726 A BR112015006726 A BR 112015006726A BR 112015006726 B1 BR112015006726 B1 BR 112015006726B1
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- Prior art keywords
- compound
- cancer
- mmol
- alkyl
- alkylene
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- 125000005842 heteroatom Chemical group 0.000 claims description 18
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
composto, composição farmacêutica, e, uso de um composto ou de uma composição farmacêutica. a presente invenção fornece derivados heteroaromáticos e sais farmacêuticos aceitáveis e formulações dos mesmos úteis na modulação da atividade da proteína cinase, especialmente fosfatidilinositol 3-cinases (pi3 cinases) e mtor e na modulação das atividades de sinalização inter- e/ou intracelulares tais como proliferação, diferenciação, apoptose, migração e invasão. a invenção também fornece composições farmaceuticamente aceitáveis que compreendem tais compostos e métodos de usar as composições no tratamento de distúrbios hiperproliferativos em mamíferos, especialmente seres humanos.compound, pharmaceutical composition, and use of a compound or pharmaceutical composition. The present invention provides pharmaceutically acceptable heteroaromatic derivatives and salts and formulations thereof useful in modulating the activity of protein kinases, especially phosphatidylinositol 3-kinases (pi3 kinases) and mtor and in modulating inter- and/or intracellular signaling activities such as proliferation , differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in treating hyperproliferative disorders in mammals, especially humans.
Description
[001] Este pedido reivindica o benefício do Pedido Provisório U.S. Serial Número 61/726.139, depositado em 14 de novembro de 2012, que é por meio deste incorporado por referência em sua totalidade.[001] This application claims the benefit of U.S. Provisional Application Serial Number 61/726,139, filed November 14, 2012, which is hereby incorporated by reference in its entirety.
[002] A invenção aqui divulgada refere-se ao campo das proteína cinases e inibidores das mesmas. Em particular, a invenção diz respeito a moduladores dos caminhos da sinalização das fosfatidilinositol 3-cinases (PI3 cinases ou PI3Ks), e métodos de uso dos mesmos.[002] The invention disclosed herein refers to the field of protein kinases and inhibitors thereof. In particular, the invention concerns modulators of the signaling pathways of phosphatidylinositol 3-kinases (PI3 kinases or PI3Ks), and methods of using them.
[003] As fosfoinositide 3-cinases (PI3 cinases ou PI3Ks), uma família de cinases de lipídeos, foram descobertas ter papéis reguladores chaves em muitos processos celulares incluindo a sobrevivência, proliferação e diferenciação celulares. Como efetores principais a jusante dos receptores das tirosina cinases (RTKs) e receptores ligados à proteína G (GPCRs), as PI3Ks transduzem sinais de vários fatores de crescimento e citocinas em mensagens intracelulares pela geração de fosfolipídeos, que ativam a proteína serina-treonina cinase AKT (também conhecida como proteína cinase B (PKB)) e outros caminhos efetores à jusante. O supressor de tumor ou PTEN (fosfatase e homólogo da tensina) é o regulador negativo mais importante do caminho da sinalização de PI3K *“Inibidores de molécula pequena da rede de sinalização de RK5M0” Future Med. Chem., 2011, 3(5), 549-565).Phosphoinositide 3-kinases (PI3 kinases or PI3Ks), a family of lipid kinases, have been discovered to have key regulatory roles in many cellular processes including cell survival, proliferation and differentiation. As major downstream effectors of receptor tyrosine kinases (RTKs) and G protein-linked receptors (GPCRs), PI3Ks transduce signals from various growth factors and cytokines into intracellular messages by generating phospholipids, which activate the protein serine-threonine kinase AKT (also known as protein kinase B (PKB)) and other downstream effector pathways. Tumor suppressor or PTEN (phosphatase and tensin homologue) is the most important negative regulator of the PI3K signaling pathway *"Small molecule inhibitors of the RK5M0 signaling network" Future Med. Chem., 2011, 3(5) , 549-565).
[004] O caminho da fosfoinositide 3-cinase (PI3K) é um caminho da transdução de sinal importante habitualmente ativado no câncer. Os caminhos de PI3K ativados levam à fosforilação de fosfatidilinositol-4,5-bisfosfato (PIP2) para gerar fosfatidilinositol-3,4,5-trisfosfato (PIP3). PIP3 pode ser desfosforilado pela fosfatase e homólogo de tensina (PTEN), que termina a sinalização de PI3K. O acúmulo de PIP3 ativa uma cascata de sinalização começando com a fosforilação (ativação) da proteína serina-treonina cinase AKT na treonina 308 pela cinase 1 dependente de fosfoinositide (PDK1). A AKT fosforilada ativa o alvo mamífero da rapamicina (mTOR), que leva à fosforilação do seu alvo à jusante.The phosphoinositide 3-kinase (PI3K) pathway is an important signal transduction pathway commonly activated in cancer. Activated PI3K pathways lead to phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 can be dephosphorylated by phosphatase and tensin homolog (PTEN), which terminates PI3K signaling. PIP3 accumulation activates a signaling cascade starting with the phosphorylation (activation) of the protein serine-threonine kinase AKT to threonine 308 by phosphoinositide-dependent kinase 1 (PDK1). Phosphorylated AKT activates the mammalian target of rapamycin (mTOR), which leads to phosphorylation of its downstream target.
[005] Existem três classes de PI3K, com estruturas e características diferentes; a classe I pode ser subdividida ainda em classe Ia e classe Ib. A PI3Ks da classe II são proteínas grandes (170 a 210 kDa) que têm um dos domínios catalíticos que medeiam a ligação de cálcio/lipídeo nas isoformas C da proteína cinase C clássica. As PI3Ks classe III são tipificadas pela proteína de levedura codificada pelo gene VPS34 e fosforila apenas PtdIns para produzir PtdIns(3)P; elas são consideradas regular o transporte vesical (Targeting PI3K signaling in cancer: opportunities, challenges and limitationSo” Nature Review Cancer, 2009, 9, 550).[005] There are three classes of PI3K, with different structures and characteristics; class I can be further subdivided into class Ia and class Ib. Class II PI3Ks are large proteins (170 to 210 kDa) that have one of the catalytic domains that mediate calcium/lipid binding in C isoforms of classical protein kinase C . Class III PI3Ks are typified by the yeast protein encoded by the VPS34 gene and phosphorylates only PtdIns to produce PtdIns(3)P; they are considered to regulate bladder transport (Targeting PI3K signaling in cancer: opportunities, challenges and limitationsSo” Nature Review Cancer, 2009, 9, 550).
[006] As PI3Ks classe Ia *RK5Mg, RK5Mβ, RK5My e RK5Mh+ compreende heterodímeros entre uma subunidade catalítica de p110 *r332g. r332β, r332y e r332h respectivamente), e uma das subunidades adaptadoras reguladoras p85 (isto é, r:7g, r:7β, r77h, r77g e r72g+0 A subunidade p110 catalítica usa ATP para fosforilar Ptdlns, PtdIns4P e PtdIns(4,5)P2. A importância das PI3Ks Classe Ia no câncer foi confirmada pela descoberta de que o gene da isoforma g da subunidade catalítica PI3K (PIK3CA), que codifica p110 , é frequentemente mutado ou amplificado em vários tumores humanos tais como câncer ovariano (Campbell et al, Cancer Res 2004, 64, 7678-7681 ; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005, 97, 26-34), câncer cervical, câncer mamário (Bachman, et al. Cancer Biol Ther 2004, 3, 772775; Levine, et al., supra; Li et al., Breast Cancer Res Treat 2006, 96, 91-95; Saal et al., Cancer Res 2005, 65, 2554-2559; Samuels e Velculescu, Cell Cycle 2004, 3, 1221-1224), câncer colorretal (Samuels, et al. Science 2004, 304, 554; Velho et al. Eur J Cancer 2005, 41, 1649-1654), câncer endometrial (Oda et al. Cancer Res. 2005, 65, 10669-10673), carcinomas gástricos (Byun et al., M J Cancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene 2005, 24, 1477-1480), carcinoma hepatocelular (Lee et al., id), câncer pulmonar de célula pequena e não pequena (Tang et al., Lung Cancer 2006, Jl, 181-191; Massion et al., Am J Respir Crit Care Meaf 2004, 1 70, 1088-1094), carcinoma tireoidal (Wu et al, J Clin Endocrinol Metab 2005, 90, 4688-4693), leucemia mielógena aguda (AML) (Sujobert et al., Blood 1997, 106, 1063-1066), leucemia mielógena crônica (CML) (Hickey e Cotter J Biol Chem 2006, 281, 2441-2450), e glioblastomas (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642; Samuels et al., supra).The class Ia PI3Ks *RK5Mg, RK5Mβ, RK5My and RK5Mh+ comprise heterodimers between a catalytic subunit of p110 *r332g. r332β, r332y and r332h respectively), and one of the p85 regulatory adapter subunits (ie, r:7g, r:7β, r77h, r77g and r72g+0 The catalytic p110 subunit uses ATP to phosphorylate Ptdlns, PtdIns4P and PtdIns 5) P2. The importance of Class Ia PI3Ks in cancer was confirmed by the discovery that the PI3K catalytic subunit g isoform gene (PIK3CA), which encodes p110, is often mutated or amplified in various human tumors such as ovarian cancer (Campbell et al, Cancer Res 2004, 64, 7678-7681 ; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005 , 97, 26-34), cervical cancer, breast cancer (Bachman, et al. Cancer Biol Ther 2004, 3, 772775; Levine, et al., supra; Li et al., Breast Cancer Res Treat 2006, 96, 91 -95; Saal et al., Cancer Res 2005, 65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224), colorectal cancer ( Samuels, et al. Science 2004, 304, 554; Velho et al. al.Eur J Cancer 200 5, 41, 1649-1654), endometrial cancer (Oda et al. Cancer Res. 2005, 65, 10669-10673), gastric carcinomas (Byun et al., MJ Cancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee et al., id), small and non-small cell lung cancer (Tang et al., Lung Cancer 2006, Jl, 181-191; Massion et al., Am J Respir Crit Care Meaf 2004, 170, 1088-1094), thyroid carcinoma (Wu et al, J Clin Endocrinol Metab 2005, 90, 4688-4693), acute myelogenous leukemia (AML) (Sujobert et al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML) (Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642; Samuels et al., supra).
[007] mTOR é uma serina-treonina cinase altamente conservada com atividade de cinase lipídica e participa como um efetor no caminho PI3K/AKT. mTOR existe em dois complexos distintos, mTORC1 e mTORC2, e desempenha um papel importante na proliferação celular pelo monitoramento da disponibilidade de nutriente e níveis de energia celular. Os alvos a jusante de mTORC1 são proteína ribossômica S6 cinase 1 e proteína 1 de ligação do fator 4E de iniciação da tradução eucariótica, ambas das quais são cruciais para a regulagem da síntese de proteína. *“Rtgugnt and future of PI3K pathway inhibition in cancer: perspectives and limitationso” Current Med. Chem. 2011, 18, 2647-2685).[007] mTOR is a highly conserved serine-threonine kinase with lipid kinase activity and participates as an effector in the PI3K/AKT pathway. mTOR exists in two distinct complexes, mTORC1 and mTORC2, and plays an important role in cell proliferation by monitoring nutrient availability and cellular energy levels. The downstream targets of mTORC1 are ribosomal protein S6 kinase 1 and eukaryotic translation initiation factor 4E binding protein 1, both of which are crucial for the regulation of protein synthesis. *“Rtgugnt and future of PI3K inhibition pathway in cancer: perspectives and limitations” Current Med. Chem. 2011, 18, 2647-2685).
[008] O conhecimento a cerca das consequências da sinalização de mTOR desregulada para a tumorigênese se origina principalmente dos estudos de interrupção por meios farmacológicos de mTOR pela repamicina e seus análogos tais como temsirolimus (CCI-779) e everolimus (RAD001). A rapamicina foi descoberta inibir mTOR e deste modo induzir a para de G1 e apoptose. O mecanismo da inibição do crescimento pela rapamicina foi descoberto estar relacionado com a formação de complexos de rapamicina com a proteína 12 que liga FK (FKBP-12). Estes complexos depois ligam com alta afinidade ao mTOR, impedindo a ativação e resultando na inibição da tradução de proteína e crescimento celular. Os efeitos celulares da inibição de mTOR são ainda mais pronunciados nas células que tenham a inativação concomitante de PTEN. A atividade antitumor da rapamicina foi subsequentemente identificada, e vários análogos da rapamicina tais como temsirolimus e everolimus foram aprovados pelo US Food and Drug Adminstration para o tratamento de certos tipos de câncer.[008] Knowledge about the consequences of deregulated mTOR signaling for tumorigenesis mainly originates from studies of pharmacologically discontinuation of mTOR by repamycin and its analogues such as temsirolimus (CCI-779) and everolimus (RAD001). Rapamycin has been found to inhibit mTOR and thereby induce G1 paralysis and apoptosis. The mechanism of growth inhibition by rapamycin was found to be related to the formation of complexes of rapamycin with FK binding protein 12 (FKBP-12). These complexes then bind with high affinity to mTOR, preventing activation and resulting in inhibition of protein translation and cell growth. The cellular effects of mTOR inhibition are even more pronounced in cells that have concomitant PTEN inactivation. Rapamycin's antitumor activity was subsequently identified, and several rapamycin analogues such as temsirolimus and everolimus were approved by the US Food and Drug Adminstration for the treatment of certain types of cancer.
[009] Em vista do papel importante das PI3Ks e mTOR nos processos biológicos e estados de doença, inibidores destas cinases são desejáveis fTosfatidilinositol 3-cinase isoforms asa novel drug VctigVUo” Current Drug Targets, 2011, 12, 1056-1081; “Rtqitess in the preclinical discovery and clinical development of class I e dual class I/IV fosfoinositide 3-cinase (PI3K) inhibitors0” Current Med Chem 2011, 18, 2686-2714).[009] In view of the important role of PI3Ks and mTOR in biological processes and disease states, inhibitors of these kinases are desirable. “Rtqitess in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors0” Current Med Chem 2011, 18, 2686-2714).
[0010] O que segue apenas resume certos aspectos da invenção e não é intencionado a ser limitante por natureza. Estes aspectos e outros aspectos e formas de realização são descritos mais completamente abaixo. Todas as referências citadas neste relatório descritivo são por meio deste incorporadas por referência em sua totalidade. No evento de uma discrepância entre a divulgação expressa deste relatório descritivo e as referências incorporadas por referência, a divulgação expressa deste relatório descritivo deve controlar.[0010] The following only summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below. All references cited in this specification are hereby incorporated by reference in their entirety. In the event of a discrepancy between the express disclosure of this descriptive report and the references incorporated by reference, the express disclosure of this descriptive report shall control.
[0011] São aqui fornecidos compostos que inibem, regulam, e/ou modulam PI3K e/ou mTOR, e são úteis no tratamento de doenças hiperproliferativas, tais como o câncer, nos seres humanos. Também são aqui fornecidos métodos de fabricar o composto, métodos de usar tais compostos no tratamento de doenças hiperproliferativas em seres humanos e composições farmacêuticas contendo tais compostos.Provided herein are compounds that inhibit, regulate, and/or modulate PI3K and/or mTOR, and are useful in the treatment of hyperproliferative diseases, such as cancer, in humans. Also provided herein are methods of making the compound, methods of using such compounds in the treatment of hyperproliferative diseases in humans, and pharmaceutical compositions containing such compounds.
[0012] O primeiro aspecto da invenção fornece um composto da Fórmula (I): ou um estereoisômero, um isômero geométrico, um tautômero, um N-óxido, um solvato, um metabólito, um sal farmacêutico ou um pró-medicamento dos mesmos, em que cada um de Y, Z, R1, W1, W2 e W3 é como aqui definido.[0012] The first aspect of the invention provides a compound of Formula (I): or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutical salt, or a prodrug thereof, wherein each of Y, Z, R1, W1, W2 and W3 is as defined herein.
[0013] Em certas formas de realização, cada um de W1, W2 e W3 é independentemente N ou CRc;[0013] In certain embodiments, each of W1, W2 and W3 is independently N or CRc;
[0014] Z é D, CN, N3 ou;[0014] Z is D, CN, N3 or ;
[0015] X é H, D, alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), -alquileno (C1-C4)- heterociclila (C3-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionado de O, S e N, em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), -alquileno (C1- C4)-heterociclila (C3-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1-C6), alquenila (C2-C6), alquinila (C2-C6), -alquileno (C1-C4)-CN, -alquileno (C1-C4)-ORa, -alquileno (C1-C4)-NRaRb, arila (C6-C10) e heteroarila de 5 a 10 membros;[0015] X is H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene(C1-C4)-cycloalkyl(C3-C6), -alkylene(C1- C4)- heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each is (C1-alkyl) C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3-C6), aryl (C6 -C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb , alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2-C6), -alkylene (C1-C4)-CN, -alkylene (C1-C4)-ORa, - (C1-C4)alkylene-NRaRb, (C6-C10) aryl, and 5- to 10-membered heteroaryl;
[0016] Y é alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), -alquileno (C1-C4)-heterociclila (C3C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), - alquileno (C1-C4)-heterociclila (C3-C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1C6), alquenila (C2-C6), alquinila (C2-C6), -alquileno (C1-C4)-CN, -alquileno (C1-C4)-ORa, -alquileno (C1-C4)-NRaRb, arila (C6-C10) e heteroarila de 5 a 10 membros;[0016] Y is alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, in that each of alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), - alkylene (C1-C4)-heterocyclyl ( C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F , Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1C6), alkenyl (C2-C6), alkynyl (C2-C6), - (C 1 -C 4 )alkylene-CN, -(C 1 -C 4 )alkylene-ORa, -(C 1 -C 4 )alkylene-NRaRb, (C 6 -C 10 ) aryl, and 5- to 10-membered heteroaryl;
[0017] R1 é H, D, Cl, ORa, NRaRb, alífático (C1-C6) ou cicloalquila (C3-C6), em que cada um do alífático (C1-C6) e cicloalquila (C3-C6) é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, CN, N3, ORa, SRa e NRaRb, contanto que quando cada um de W1, W2 e W3 é CH, R1 não é H ou NH2;[0017] R1 is H, D, Cl, ORa, NRaRb, aliphatic (C1-C6) or cycloalkyl (C3-C6), wherein each of the aliphatic (C1-C6) and cycloalkyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, ORa, SRa and NRaRb, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2;
[0018] Cada um de Ra e Rb é independentemente H, alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), arila (C6-C10), heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, -alquileno (C1-C4)-arila (C6-C10) ou -alquileno (C1- C4)-(heteroarila de 5 a 10 membros); ou quando Ra e Rb são ligados ao mesmo átomo de nitrogênio, Ra e Rb, junto com o átomo de nitrogênio ao qual eles estão ligados, opcionalmente formam um anel heterocíclico de 3 a 8 membros substituído ou não substituído, em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, CN, N3, OH, NH2, (C1- C6)alcóxi, e alquila (C1-C6) amino; e[0018] Each of Ra and Rb is independently H, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, -(C 1 -C 4 )alkylene- (C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(5- to 10-membered heteroaryl); or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb, together with the nitrogen atom to which they are attached, optionally form a substituted or unsubstituted 3- to 8-membered heterocyclic ring, wherein each of the alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, (C1-C6)alkoxy, and (C1-C6)alkylamino; and
[0019] cada Rc é independentemente H, D, F, Cl, Br, I, N3, CN, OH, NH2, alquila (C1-C6), alcóxi (C1-C6), alquila (C1-C6) amino, cicloalquila (C3C6), heterociclila (C3-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, em que cada um do alquila (C1-C6), alcóxi (C1-C6), alquila (C1-C6) amino, cicloalquila (C3-C6), heterociclila (C3-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, CN, N3, OH, NH2, alquila (C1C6), cicloalquila (C3-C6), haloalquila (C1-C6), alcóxi (C1-C6) e alquila (C1-C6) amino.[0019] each Rc is independently H, D, F, Cl, Br, I, N3, CN, OH, NH2, alkyl (C1-C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3C6), heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, where each of (C1) alkyl -C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, alkyl (C1C6), cycloalkyl (C3-C6), haloalkyl (C1-C6), alkoxy (C1-C6) and (C1-C6) alkylamino.
[0020] Em uma outra forma de realização, cada um de W1 e W2 é independentemente N ou CRc, W3 é CRc.[0020] In another embodiment, each of W1 and W2 is independently N or CRc, W3 is CRc.
[0021] Em uma outra forma de realização, Z é CN, N3 ou’^ x.[0021] In another embodiment, Z is CN, N3 or ’^x.
[0022] Em uma outra forma de realização, X é H, D, alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3C6) ou -alquileno (C1-C4)-heterociclila (C3-C6), em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)- cicloalquila (C3-C6) e -alquileno (C1-C4)-heterociclila (C3-C6) é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1-C6), alquenila (C2-C6) e alquinila (C2-C6).[0022] In another embodiment, X is H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3C6) or -(C1-C4)alkylene-(C3-C6)heterocyclyl, wherein each of (C1-C6)alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclyl, (C1-C4)alkylene-cycloalkyl (C3-C6) and -(C1-C4)alkylene-heterocyclyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa , NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6) and alkynyl (C2-C6).
[0023] Em uma outra forma de realização, Y é alquila (C1-C6), cicloalquila (C3-C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, em que cada um do alquila (C1C6), cicloalquila (C3-C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1-C6), alquinila (C2C6), arila (C6-C10) e heteroarila de 5 a 10 membros.[0023] In another embodiment, Y is alkyl (C1-C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10), or heteroaryl of 5 to 10 members comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of alkyl (C1C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6 ), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C (=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkynyl (C2C6), aryl (C6-C10) and 5- to 10-membered heteroaryl.
[0024] Em uma outra forma de realização, R1 é H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3, OCH2CH3, NH2, NHCH3 ou N(CH3)2, contanto que quando cada um de W1, W2 e W3 for CH, R1 não é H ou NH2.[0024] In another embodiment, R1 is H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3, OCH2CH3, NH2, NHCH3 or N(CH3)2, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2.
[0025] Em uma outra forma de realização, cada Rc é independentemente H, D, F, Cl, N3, CN, NH2, alquila (C1-C3), alcóxi (C1-C3), alquila (C1-C3) amino, cicloalquila (C3-C6) ou heterociclila (C3-C6), em que cada um do alquila (C1-C3), alcóxi (C1-C3), alquila (C1-C3) amino, cicloalquila (C3-C6) e heterociclila (C3-C6) é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, CN, N3, OH, NH2, alquila (C1-C3), cicloalquila (C3-C6) e haloalquila (C1-C3).[0025] In another embodiment, each Rc is independently H, D, F, Cl, N3, CN, NH2, alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) or heterocyclyl (C3-C6), wherein each of alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) and heterocyclyl ( C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CN, N3, OH, NH2, alkyl (C1-C3), cycloalkyl (C3-C6) and haloalkyl (C1-C3 ).
[0026] Em um outro aspecto, são aqui fornecidas composições farmacêuticas compreendendo um composto aqui divulgado, ou um estereoisômero, isômero geométrico, tautômero, solvato, metabólito, sal ou pró-medicamento farmaceuticamente aceitáveis dos mesmos, e um carregador, excipiente, diluente, adjuvante, veículo farmaceuticamente aceitáveis opcionais ou uma combinação dos mesmos. Em certas formas de realização, o composto é um modulador de PI3K.[0026] In another aspect, provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable stereoisomer, geometric isomer, tautomer, solvate, metabolite, salt or prodrug thereof, and a carrier, excipient, diluent, optional pharmaceutically acceptable adjuvant, carrier or a combination thereof. In certain embodiments, the compound is a PI3K modulator.
[0027] Em algumas formas de realização, a composição farmacêutica aqui divulgada compreende ainda um agente terapêutico adicional. Em outras formas de realização, o agente terapêutico é um agente quimioterapêutico, um agente antiproliferativo, um agente para tratar a aterosclerose, um agente para tratar fibrose pulmonar ou uma combinação dos mesmos.[0027] In some embodiments, the pharmaceutical composition disclosed herein further comprises an additional therapeutic agent. In other embodiments, the therapeutic agent is a chemotherapeutic agent, an anti-proliferative agent, an agent to treat atherosclerosis, an agent to treat pulmonary fibrosis, or a combination thereof.
[0028] Em certas formas de realização, o agente terapêutico adicional é clorambucila, melfalan, ciclofosfamida, ifosfamida, busulfan, carmustina, lomustina, estreptozocina, cisplatina, carboplatina, oxaliplatina, dacarbazina, temozolomida, procarbazina, metotrexato, fluorouracila, citarabina, gencitabina, mercaptopurina, fludarabina, vinblastina, vincristina, vinorrelbina, paclitaxel, docetaxel, topotecano, irinotecano, etoposida, trabectedina, dactinomicina, doxorrubicina, epirrubicina, daunorrubicina, mitoxantrona, bleomicina, mitomicina, ixabepilona, tamoxifeno, flutamida, análogos de gonadorelina, megestrol, prednidona, dexametasona, metilprednisolona, talidomida, interferon alfa, leucovorina, sirolimus, tensirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, tositumomab, trastuzumab, ou uma combinação dos mesmos.In certain embodiments, the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocine, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracila, citea mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, gooxitambemcin, fludomycin, bleomycin, mitoxitamycin, fludomycin, fludomycin dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, tensirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cedibtinib dab, dabtininib, cretinib, dabtininib, dab erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotin ib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, sarertinib, rego sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab, brentuximab, tumabximab, tumaboxime, cathuzuma, , rituximab, tositumomab, trastuzumab, or a combination thereof.
[0029] Em um outro aspecto, são aqui fornecidos métodos para prevenir, controlar, tratar ou diminuir a severidade de um distúrbio proliferativo em um paciente infectado com o distúrbio proliferativo, que compreende administrar uma quantidade farmaceuticamente eficaz do composto aqui divulgado, ou da composição farmacêutica aqui divulgada ao paciente.[0029] In another aspect, provided herein are methods for preventing, controlling, treating or lessening the severity of a proliferative disorder in a patient infected with the proliferative disorder, which comprises administering a pharmaceutically effective amount of the compound disclosed herein, or the composition pharmaceutical here disclosed to the patient.
[0030] Em um outro aspecto, é aqui fornecido o uso do composto aqui divulgado, ou da composição farmacêutica aqui divulgada na fabricação de um medicamento para prevenir, controlar, tratar ou diminuir a severidade de um distúrbio proliferativo em um paciente.[0030] In another aspect, provided herein is the use of the compound disclosed herein, or the pharmaceutical composition disclosed herein, in the manufacture of a medicament for preventing, controlling, treating or lessening the severity of a proliferative disorder in a patient.
[0031] Em algumas formas de realização, o distúrbio proliferativo é câncer metastático. Em outras formas de realização, o distúrbio proliferativo é câncer de cólon, adenocarcinoma gástrico, câncer de bexiga, câncer mamário, câncer renal, câncer hepático, câncer pulmonar, câncer de pele, câncer da tireóide, câncer da cabeça e pescoço, câncer da próstata, câncer pancreático, câncer do CNS, glioblastoma ou um distúrbio mieloproliferativo. Em outras formas de realização, o distúrbio proliferativo é aterosclerose ou fibrose pulmonar.[0031] In some embodiments, the proliferative disorder is metastatic cancer. In other embodiments, the proliferative disorder is colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer , pancreatic cancer, CNS cancer, glioblastoma or a myeloproliferative disorder. In other embodiments, the proliferative disorder is atherosclerosis or pulmonary fibrosis.
[0032] Em um outro aspecto, é aqui fornecido um método de inibir ou modular a atividade de PI3K e/ou mTOR em um amostra biológica compreendendo contatar uma amostra biológica com o composto aqui divulgado, ou a composição farmacêutica aqui divulgada.[0032] In another aspect, provided herein is a method of inhibiting or modulating the activity of PI3K and/or mTOR in a biological sample comprising contacting a biological sample with the compound disclosed herein, or the pharmaceutical composition disclosed herein.
[0033] Em algumas formas de realização, é aqui fornecido um método de inibir ou modular PI3K ou mTOR, o método compreendendo contatar a cinase com o composto de acordo com a presente invenção, ou com a composição de acordo com a presente invenção. Em algumas formas de realização, a invenção fornece um método de inibir ou modular a sinalização de PI3K ou mTOR, o método compreendendo contatar o receptor com o composto de acordo com a presente invenção, ou com a composição de acordo com a presente invenção. Em algumas formas de realização, a inibição ou modulação da atividade de PI3K ou mTOR pode ser em uma célula ou um organismo multicelular. Se em um organismo multicelular, o método de acordo com este aspecto da invenção compreende administrar ao organismo o composto de acordo com a presente invenção, ou a composição de acordo com a presente invenção. Em algumas formas de realização, o organismo é um mamífero. Em outras formas de realização é um ser humano. Ainda em outra forma de realização, o método compreende ainda contatar a cinase com um agente terapêutico adicional.In some embodiments, provided herein is a method of inhibiting or modulating PI3K or mTOR, the method comprising contacting the kinase with the compound according to the present invention, or with the composition according to the present invention. In some embodiments, the invention provides a method of inhibiting or modulating PI3K or mTOR signaling, the method comprising contacting the receptor with the compound according to the present invention, or with the composition according to the present invention. In some embodiments, the inhibition or modulation of PI3K or mTOR activity can be in a cell or a multicellular organism. If in a multicellular organism, the method according to this aspect of the invention comprises administering to the organism the compound according to the present invention, or the composition according to the present invention. In some embodiments, the organism is a mammal. In other embodiments it is a human. In yet another embodiment, the method further comprises contacting the kinase with an additional therapeutic agent.
[0034] Em um outro aspecto, é aqui fornecido um método de inibir a atividade proliferativa de uma célula, o método compreendendo contatar a célula com uma quantidade inibidora proliferativa eficaz de um composto de acordo com a presente invenção ou uma composição do mesmo. Em algumas formas de realização, o método compreende ainda contatar a célula com um agente terapêutico adicional.[0034] In another aspect, provided herein is a method of inhibiting the proliferative activity of a cell, the method comprising contacting the cell with an effective proliferative inhibitory amount of a compound according to the present invention or a composition thereof. In some embodiments, the method further comprises contacting the cell with an additional therapeutic agent.
[0035] Em um outro aspecto, é aqui fornecido um método de tratar uma doença de célula proliferativa em um paciente, o método compreendendo administrar ao paciente em necessidade de tal tratamento uma quantidade terapêutica eficaz do composto de acordo com a presente invenção ou a composição do mesmo. Em algumas formas de realização, o método compreende ainda administrar um agente terapêutico adicional.[0035] In another aspect, provided herein is a method of treating a cell proliferative disease in a patient, the method comprising administering to the patient in need of such treatment a therapeutically effective amount of the compound according to the present invention or the composition the same. In some embodiments, the method further comprises administering an additional therapeutic agent.
[0036] Em algumas formas de realização, é aqui fornecido um método de inibir crescimento de tumor em um paciente, o método compreendendo administrar ao paciente em necessidade do mesmo uma quantidade terapêutica eficaz do composto de acordo com a presente invenção ou a composição dos mesmos. Em algumas formas de realização, o método compreende ainda administrar um agente terapêutico adicional.[0036] In some embodiments, provided herein is a method of inhibiting tumor growth in a patient, the method comprising administering to the patient in need thereof an effective therapeutic amount of the compound according to the present invention or the composition thereof . In some embodiments, the method further comprises administering an additional therapeutic agent.
[0037] Em um outro aspecto, aqui fornecido inclui métodos de preparar, métodos de separar, e métodos de purificar compostos da Fórmula (I).[0037] In another aspect, provided herein includes methods of preparing, methods of separating, and methods of purifying compounds of Formula (I).
[0038] O precedente meramente resume certos aspectos da invenção e não é intencionado a ser limitante por natureza. Estes aspectos e outros aspectos e formas de realização são descritos mais completamente abaixo.[0038] The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.
[0039] Referência será feita agora em detalhes a certas formas de realização da invenção, os exemplos das quais são ilustradas nas estruturas e fórmulas anexas. A invenção é intencionada a abranger toda as alternativas, modificações, e equivalentes que possam ser incluídas dentro do escopo da presente invenção como definido pelas reivindicações. Uma pessoa de habilidade na técnica reconhecerá muitos métodos e materiais similares ou equivalentes a aqueles aqui descritos, que podem ser usados na prática da presente invenção. A presente invenção não é de nenhum modo limitada aos métodos e materiais aqui descritos. No evento que um ou mais da literatura, patentes, e materiais similares incorporados diferem de ou contradizem este pedido, incluindo mas não limitado aos termos, uso de termo, técnicas descritas, ou os semelhantes definidos, este pedido controla.[0039] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the appended structures and formulas. The invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined by the claims. A person of skill in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differ from or contradict this application, including but not limited to the terms, term usage, described techniques, or the like as defined, this application governs.
[0040] A menos que de outro modo definido, todos os termos técnicos e científicos aqui usados têm o mesmo significado como é habitualmente entendido por uma pessoa de habilidade na técnica à qual esta invenção pertence. Todas as patentes e publicações aqui aludidas são incorporadas por referência.[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of skill in the art to which this invention belongs. All patents and publications referenced herein are incorporated by reference.
[0041] Como aqui usado, as seguintes definições devem se aplicar a menos que de outro modo indicado. Para os propósitos desta invenção, os elementos químicos são identificados de acordo com a Tabela Periódica dos Elementos, versão CAS, e o Handbook of Chemistry and Physics, 75a Ed. 1994. Adicionalmente, os princípios gerais da química orgânica são descritos em “Qtiâpke EjgoiuVty” Thomas Sorrell, University Science Books, Sausalito: 1999, e “Marcus Advanced Organic EjgokuVty” por Michael B. Smith e Jerry March, John Wiley & Sons, Nova Iorque: 2007, os conteúdos inteiros dos quais são por meio deste incorporados por referência.[0041] As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in "Qtiâpke EjgoiuVty ” Thomas Sorrell, University Science Books, Sausalito: 1999, and “Marcus Advanced Organic EjgokuVty” by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are hereby incorporated by reference .
[0042] Como usado no relatório descritivo e reivindicações, o termo “um,” “uma,” “o/a” e termos similares usados no contexto da presente invenção devem ser interpretados abranger tanto o singular quanto o plural a menos que de outro modo aqui indicado ou claramente contradito pelo contexto.[0042] As used in the specification and claims, the term "a," "an," "the" and similar terms used in the context of the present invention shall be interpreted to encompass both the singular and the plural unless otherwise noted. here indicated or clearly contradicted by the context.
[0043] Como aqui usado, o termo “indivíduo” refere-se a um animal. Tipicamente o animal é um mamífero. Um indivíduo também se refere a por exemplo, primatas (por exemplo, seres humanos, do sexo masculino ou feminino), gado bovino, ovelha, cabras, cavalos, cães, gatos, coelhos, ratos, camundongos, peixe, pássaros e os semelhantes. Em certas formas de realização, o indivíduo é um primata. Já em outras formas de realização, o indivíduo é um ser humano.[0043] As used herein, the term "individual" refers to an animal. Typically the animal is a mammal. An individual also refers to, for example, primates (eg, humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human being.
[0044] Como aqui usado, “paciente” refere-se a um ser humano (incluindo adultos e crianças) ou outro animal. Em uma forma de realização, “paciente” refere-se a um ser humano.[0044] As used herein, "patient" refers to a human (including adults and children) or other animal. In one embodiment, "patient" refers to a human being.
[0045] A presente invenção também inclui compostos isotopicamente rotulados, que são idênticos a aqueles aqui citados, a não ser pelo fato de que um ou mais átomos são substituídos por um átomo tendo uma massa atômica ou número de massa diferente da massa atômica ou número de massa usualmente encontrados na natureza. Alguns exemplos não limitantes de isótopos que podem ser incorporados nos compostos aqui divulgados incluem isótopos de hidrogênio, carbono, nitrogênio, oxigênio, fósforo, flúor e cloro, 2 3 13 14 15 17 18 31 32 36 18 37 tal como H, H, C, C, N, O, O, P, P, S, F, e Cl.[0045] The present invention also includes isotopically labeled compounds, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or number of mass usually found in nature. Some non-limiting examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, 2 3 13 14 15 17 18 31 32 36 18 37 such as H, H, C , C, N, O, O, P, P, S, F, and Cl.
[0046] Os compostos aqui divulgados que contêm os isótopos anteriormente mencionados e/ou outros isótopos de outros átomos estão dentro do escopo desta invenção. Certos compostos isotopicamente rotulados aqui divulgados, por exemplo aqueles nos quais isótopos radioativos tais como 3H e 14C são incorporados, são úteis nos ensaios de distribuição de medicamento e/ou tecido de substrato. Os isótipos tritiados, isto é, 3H, e carbono-14, isto é, 14C, são particularmente preferidos quanto à sua facilidade de preparação e detecção. Além disso, a substituição com isótopos mais pesados tais como deutério, isto é, 2H, pode proporcionar certas vantagens terapêuticas que resultam de maior estabilidade metabólica, por exemplo exigências aumentadas na meia-vida in vivo ou de dosagem reduzida e, consequentemente, pode ser preferida em algumas circunstâncias.[0046] The compounds disclosed herein which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds disclosed herein, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotypes are particularly preferred for their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic advantages that result from greater metabolic stability, for example increased requirements on in vivo half-life or reduced dosage and, consequently, may be preferred in some circumstances.
[0047] As definições e convenções estereoquímicas aqui usadas no geral seguem S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, Nova Iorque; e Eliel, E. e Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., Nova Iorque, 1994. Muitos compostos orgânicos existem nas formas oticamente ativas, isto é, elas têm a capacidade para girar o plano de luz polarizada no plano. Na descrição de um composto opticamente ativo, os prefixos D e L, ou R e S, são usados para indicar a configuração absoluta da molécula em torno do seu(s) centro(s) quiral(is). Os prefixos d e l ou (+) e (-) são utilizados para designar o sinal de rotação da luz polarizada no plano pelo composto, com (-) ou l significando que o composto é levorrotatório. Um composto prefixado com (+) ou d é dextrorrotatório. Para uma dada estrutura química, estes estereoisômeros são idênticos exceto que eles são imagens de espelho um do outro. Um estereoisômero específico também pode ser aludido como um enantiômero, e uma mistura de tais isômeros é frequentemente chamada de uma mistura enantiomérica. Uma mistura 50:50 de enantiômeros é aludida como uma mistura racêmica ou um racemato, que pode ocorrer onde não houve nenhuma estereosseleção ou estereoespecificidade em uma reação ou processo químicos.Stereochemical definitions and conventions used generally herein follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane polarized light in the plane. In describing an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
[0048] Dependendo da escolha dos materiais de partida e procedimentos, os compostos podem estar presentes na forma de um dos isômeros possíveis ou como misturas dos mesmos, por exemplo como isômeros ópticos puros, ou como misturas de isômero, tais como racematos e misturas de diaestereoisômero, dependendo do número de átomos de carbono assimétricos. Os isômeros (R) e (S) opticamente ativos podem ser preparados usando sintons quirais ou reagentes quirais, ou resolvidos usando técnicas convencionais. Se o composto contém uma ligação dupla, o substituinte pode ser da configuração E ou Z. Se o composto contém um cicloalquila dissubstituído, o substituinte de cicloalquila pode ter uma configuração cis ou trans.[0048] Depending on the choice of starting materials and procedures, the compounds may be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and mixtures of diastereoisomer, depending on the number of asymmetric carbon atoms. Optically active (R) and (S) isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be of the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.
[0049] Os compostos aqui divulgados podem conter centros assimétricos ou quirais, e portanto existem nas formas estereoisoméricas diferentes. É intencionado que todas as formas estereoisoméricas dos compostos aqui divulgados, incluindo mas não limitado a, diastereômeros, enantiômeros, atropisômeros, e isômeros geométricos (ou conformacionais) assim como misturas dos mesmos tais como misturas racêmicas, façam parte da presente invenção.The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers as well as mixtures thereof such as racemic mixtures, form part of the present invention.
[0050] A menos que de outro modo estabelecido, as estruturas aqui representadas também são intencionadas a incluir todas as formas isoméricas (por exemplo, enantiomérica, diastereomérica, atropisomérica e geométrica (ou conformacional)) da estrutura; por exemplo, as configurações R e S para cada centro assimétrico, isômeros de ligação dupla (Z) e (E), e isômeros conformacionais (Z) e (E).Unless otherwise stated, structures depicted herein are also intended to include all isomeric forms (e.g., enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational)) of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers (Z) and (E), and conformational isomers (Z) and (E).
[0051] O termo “tautômero” ou “forma tautomérica” refere-se a isômeros estruturais de energias diferentes que são interconversíveis por intermédio de uma barreira de baixa energia. Onde a tautomerização é possível (por exemplo em solução), um equilíbrio químico de tautômeros pode ser atingido. Por exemplo, tautômeros de próton (também conhecidos como tautômeros prototrópicos) incluem interconversões por intermédio da migração de um próton, tal como isomerizações de ceto-enol e imina- enamina. Tautômeros de valência incluem interconversões pela reorganização de alguns dos elétrons de união. Um exemplo específico de tautomerização de ceto-enol é a interconversão de tautômeros de pentano-2,4-diona e 4- hidroxipent-3-en-2-ona. um outro exemplo de tautomerização é a tautomerização de fenol-ceto. Um exemplo específico de tautomerização de fenol-ceto é a interconversão de tautômeros de piridin-4-ol e piridin-4(1H)- ona.[0051] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. Where tautomerization is possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by the reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
[0052] A menos que de outro modo estabelecido, todas as formas tautoméricas dos compostos aqui divulgados estão dentro do escopo da invenção. Adicionalmente, a menos que de outro modo estabelecido, as estruturas aqui representadas são também intencionadas a incluir compostos que diferem apenas na presença de um ou mais átomos isotopicamente enriquecidos.Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.
[0053] Qualquer átomo assimétrico (por exemplo, carbono ou os semelhantes) do(s) composto(s) da presente invenção pode estar presente na racêmica ou enantiomericamente enriquecida, por exemplo na configuração (R), (S) ou (R,S). Em certas formas de realização, cada átomo assimétrico tem pelo menos 50 % de excesso enantiomérico, pelo menos 60 % de excesso enantiomérico, pelo menos 70 % de excesso enantiomérico, pelo menos 80 % de excesso enantiomérico, pelo menos 90 % de excesso enantiomérico, pelo menos 95 % de excesso enantiomérico, ou pelo menos 99 % de excesso enantiomérico na configuração (R) ou (S). Os substituintes nos átomos com ligações duplas insaturadas, se possível, podem estar presentes na forma cis (Z) ou trans (E).[0053] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention may be present in the racemic or enantiomerically enriched, e.g. S). In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) or (S) configuration. Substituents on atoms with unsaturated double bonds, if possible, may be present in cis (Z) or trans (E) form.
[0054] Consequentemente, como aqui usado um composto aqui divulgado pode estar na forma de um dos isômeros possíveis, rotâmeros, atropisômeros, tautômeros ou misturas dos mesmos, por exemplo, como isômeros geométricos substancialmente puros (cis ou trans), diastereômeros, isômeros ópticos (antípodes), racematos ou misturas dos mesmos.Accordingly, as used herein a compound disclosed herein may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric isomers (cis or trans), diastereomers, optical isomers (antipods), racemates or mixtures thereof.
[0055] Qualquer uma das misturas resultantes de isômeros pode ser separada com base nas diferenças físico-químicas dos constituintes, nos isômeros geométricos ou ópticos puros ou substancialmente puros, diastereômeros, racematos, por exemplo, pela cromatografia e/ou cristalização fracionária.[0055] Any of the resulting mixtures of isomers can be separated based on the physicochemical differences of the constituents, on pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
[0056] Qualquer um dos racematos resultantes de produtos finais ou intermediários pode ser resolvido nos antípodes ópticos pelos métodos conhecidos por aqueles habilitados na técnica, por exemplo, pela separação dos sais diastereoméricos dos mesmos. Os produtos racêmicos também podem ser resolvidos pela cromatografia quiral, por exemplo, cromatografia líquida de alto desempenho (HPLC) usando um absorvente quiral. Os enantiômeros preferidos também podem ser preparados pela síntese assimétrica. Ver, por exemplo, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, Nova Iorque, 1981); Principles of Asymmetric Synthesis (2a Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); e Wylen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).[0056] Any of the racemates resulting from final products or intermediates can be resolved into optical antipods by methods known to those skilled in the art, for example, by separating the diastereomeric salts thereof. Racemic products can also be resolved by chiral chromatography, eg high performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wylen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
[0057] Como aqui descrito, os compostos aqui divulgados podem ser opcionalmente substituídos com um ou mais substituintes, tal como é ilustrado no geral abaixo, ou como exemplificado pelas classes, subclasses, e espécies particulares da invenção. Será avaliado que a frase “opcionalmente substituído” é usada intercambiavelmente com a frase “substituído ou não substituído”. No geral, o termo “substituído” seja precedido pelo termo “opcionalmente” ou não, refere-se à substituição de um ou mais radicais de hidrogênio em uma dada estrutura com o radical de um substituinte especificado. O termo “opcional” ou “opcionalmente” significa que o evento ou circunstância subsequentemente descritos podem mas não precisam ocorrer, e que a descrição inclui casos onde o evento ou circunstância ocorrem e casos em que não ocorrem. A menos que de outro modo indicado, um grupo opcionalmente substituído pode ter um substituinte em cada posição substituível do grupo. Quando mais do que uma posição em uma dada estrutura pode ser substituída com mais do que um substituinte selecionado de um grupo especificado, o substituinte pode ser o mesmo ou diferente em cada posição.[0057] As described herein, the compounds disclosed herein may optionally be substituted with one or more substituents, as illustrated generally below, or as exemplified by the classes, subclasses, and particular species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or not substituted”. In general, the term "substituted" whether preceded by the term "optionally" or not, refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. The term “optionally” or “optionally” means that the event or circumstance subsequently described may but need not occur, and that the description includes cases where the event or circumstance does occur and cases where it does not. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be replaced with more than one substituent selected from a specified group, the substituent may be the same or different at each position.
[0058] O termo “alquila” ou “grupo alquila” como aqui usado refere- se a um radical de hidrocarboneto monovalente saturado de cadeia linear ou ramificada de 1 a 20 átomos de carbono. A menos que de outro modo especificado, grupos alquila contêm de 1 a 20 átomos de carbono. Em algumas formas de realização, os grupos alquila contêm de 1 a 10 átomos de carbono. Em outras formas de realização, grupos alquila contêm de 1 a 8 átomos de carbono. Ainda em outras formas de realização, os grupos alquila contêm de 1 a 6 átomos de carbono. Já em outras formas de realização, os grupos alquila contêm de 1 a 4 átomos de carbono, e em outras formas de realização, os grupos alquila contêm de 1 a 3 átomos de carbono.[0058] The term "alkyl" or "alkyl group" as used herein refers to a straight or branched chain saturated monovalent hydrocarbon radical of 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In other embodiments, alkyl groups contain 1 to 8 carbon atoms. In yet other embodiments, the alkyl groups contain 1 to 6 carbon atoms. In other embodiments, alkyl groups contain 1 to 4 carbon atoms, and in other embodiments, alkyl groups contain 1 to 3 carbon atoms.
[0059] Os exemplos de grupos alquila incluem, mas não são limitados a, metila (Me, -CH3), etila (Et, -CH2CH3), 1-propila (n-Pr, n-propila, - CH2CH2CH3), 2-propila (i-Pr, i-propila, -CH(CH3)2), 1-butila (n-Bu, n-butila, -CH2CH2CH2CH3), 2-metil-1-propila (i-Bu, i-butila, -CH2CH(CH3)2), 2-butila (s-Bu, s-butila, -CH(CH3)CH2CH3), 2-metil-2-propila (t-Bu, t-butila, - C(CH3)3), 1-pentila (n-pentila, -CH2CH2CH2CH2CH3), 2-pentila (- CH(CH3)CH2CH2CH3), 3-pentila (-CH(CH2CH3)2), 2-metil-2-butila (- C(CH3)2CH2CH3), 3-metil-2-butila (-CH(CH3)CH(CH3)2), 3-metil-1-butila (- CH2CH2CH(CH3)2), 2-metil-1-butila (-CH2CH(CH3)CH2CH3), 1-hexila (- CH2CH2CH2CH2CH2CH3), 2-hexila (-CH(CH3)CH2CH2CH2CH3), 3-hexila (- CH(CH2CH3)(CH2CH2CH3)), 2-metil-2-pentila (-C(CH3)2CH2CH2CH3), 3- metil-2-pentila (-CH(CH3)CH(CH3)CH2CH3), 4-metil-2-pentila (-CH(CH3)- CH2CH(CH3)2), 3-metil-3-pentila (-C(CH3)(CH2CH3)2), 2-metil-3-pentila (- CH(CH2CH3)CH(CH3)2), 2,3-dimetil-2-butila (-C(CH3)2CH(CH3)2), 3,3- dimetil-2-butila (-CH(CH3)C(CH3)3, 1-heptila, 1-octila, e os semelhantes. Os radicais de alquila são opcionalmente substituídos independentemente com um ou mais substituintes aqui descritos.[0059] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2- propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3 ), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3 )2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH (CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)-CH2CH(CH3)2), 3-methyl -3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3 )2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH) 3)C(CH3)3, 1-heptyl, 1-octyl, and the like. Alkyl radicals are optionally independently substituted with one or more substituents described herein.
[0060] Os termos “alquila” e o prefixo “alqu-” como aqui usados, são inclusive tanto de cadeia reta e cadeia carbônica saturada ramificada.[0060] The terms "alkyl" and the prefix "alqu-" as used herein are inclusive of both straight chain and branched saturated carbon chain.
[0061] O termo “alquileno”, como aqui usado, representa um grupo de hidrocarboneto bivalente saturado derivado de um hidrocarboneto saturado de cadeia reta ou ramificada pela remoção de dois átomos de hidrogênio. A menos que de outro modo especificado, os grupos alquileno contêm de 1 a 6 átomos de carbono. Em algumas formas de realização, os grupos alquileno contêm de 1 a 4 átomos de carbono. Em outras formas de realização, os grupos alquileno contêm de 1 a 2 átomos de carbono. O grupo alquileno é exemplificado por metileno (-CH2-), etileno (-CH2CH2-), isopropileno (- CH(CH3)CH2-), e os semelhantes.[0061] The term "alkylene", as used herein, represents a saturated bivalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, alkylene groups contain 1 to 6 carbon atoms. In some embodiments, alkylene groups contain 1 to 4 carbon atoms. In other embodiments, alkylene groups contain 1 to 2 carbon atoms. The alkylene group is exemplified by methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.
[0062] O termo “alquenila” refere-se a radical de hidrocarboneto monovalente de cadeia linear ou ramificada de 2 a 12 átomos de carbono com pelo menos um sítio de insaturação, isto é, uma ligação de carbono-carbono, sp2 dupla, em que o radical alquenila pode ser opcionalmente substituído independentemente com um ou mais substituintes aqui descritos, e inclui radicais tendo orientações “eku” g “Vtcpu”, ou alternativamente, orientações “E” e “Z”. Preferivelmente, o grupo alquenila contém de 2 a 8 átomos de carbono, mais preferivelmente, de 2 a 6 átomos de carbono, e o mais preferivelmente de 2 a 4 átomos de carbono. Os exemplos incluem, mas não são limitados a, etilenila ou vinila (-CH=CH2), alila (-CH2CH=CH2), e os semelhantes.[0062] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon bond, sp2 double, in that the alkenyl radical may optionally be independently substituted with one or more substituents described herein, and includes radicals having "eku" and "Vtcpu" orientations, or alternatively, "E" and "Z" orientations. Preferably, the alkenyl group contains from 2 to 8 carbon atoms, more preferably, from 2 to 6 carbon atoms, and most preferably from 2 to 4 carbon atoms. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.
[0063] O termo “alquinila” refere-se a um radical de hidrocarboneto monovalente linear ou ramificado de 2 a 12 átomos de carbono com pelo menos um sítio de insaturação, isto é, uma ligação carbono-carbono, sp tripla, em que o radical alquinila pode ser opcionalmente substituído independentemente com um ou mais substituintes aqui descritos. Preferivelmente, o grupo alquinila contém de 2 a 8 átomos de carbono, mais preferivelmente de 2 a 6 átomos de carbono, e o mais preferivelmente de 2 a 4 átomos de carbono. Os exemplos incluem, mas não são limitados a, etinila (- EzEJ+. propinila (propargila, -CH2EzEJ+. -EzE-CH3, e os semelhantes.[0063] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon bond, sp triple, where the alkynyl radical may optionally be independently substituted with one or more substituents described herein. Preferably, the alkynyl group contains from 2 to 8 carbon atoms, more preferably from 2 to 6 carbon atoms, and most preferably from 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl (-EzEJ+, propynyl (propargyl, -CH2EzEJ+, -EzE-CH3, and the like).
[0064] Os termos “alifático” ou “grupo alifático” como aqui usados, referem-se a uma cadeia de hidrocarboneto de cadeia reta (isto é, não ramificada) ou ramificada, substituída ou não substituída que é completamente saturada ou que contém uma ou mais unidades de insaturação. A menos que de outro modo especificado, os grupo alifáticos contêm de 1 a 20 átomos de carbono. Em algumas formas de realização, os grupos alifáticos contêm de 1 a 10 átomos de carbono. Em outras formas de realização, os grupos alifáticos contêm de 1 a 8 átomos de carbono. Ainda em outra formas de realização, os grupos alifáticos contêm de 1 a 6 átomos de carbono. Já em outras formas de realização, os grupos alifáticos contêm de 1 a 4 átomos de carbono, e em outras formas de realização, os grupos alifáticos contêm de 1 a 3 átomos de carbono. Os grupos alifáticos adequados incluem, mas não são limitados a, grupos alquila, alquenila, ou alquinila lineares ou ramificados, substituídos ou não substituídos. Por exemplo, grupos alífáticos (C1-C6) incluem os grupos alquila (C1-C6), alquenila (C2-C6) ou alquinila (C2-C6) não ramificados ou ramificados, não substituídos ou adequadamente substituídos. Os grupos alifáticos aqui são opcionalmente substituídos independentemente com um ou mais substituintes aqui descritos.[0064] The terms "aliphatic" or "aliphatic group" as used herein refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains a or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1 to 20 carbon atoms. In some embodiments, aliphatic groups contain 1 to 10 carbon atoms. In other embodiments, aliphatic groups contain 1 to 8 carbon atoms. In yet other embodiments, aliphatic groups contain 1 to 6 carbon atoms. In other embodiments, aliphatic groups contain 1 to 4 carbon atoms, and in other embodiments, aliphatic groups contain 1 to 3 carbon atoms. Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted linear or branched alkyl, alkenyl, or alkynyl groups. For example, aliphatic (C1-C6) groups include unbranched or branched, unsubstituted or suitably substituted alkyl (C1-C6), alkenyl (C2-C6) or (C2-C6) alkynyl groups. Aliphatic groups herein are optionally independently substituted with one or more substituents described herein.
[0065] O termo “alcóxi” como aqui usado, refere-se a um grupo alquila, como anteriormente definido, ligado ao átomo de carbono principal através de um átomo de oxigênio. A menos que de outro modo especificado, grupos alcóxi contêm de 1 a 20 átomos de carbono. Em algumas formas de realização, os grupos alcóxi contêm de 1 a 10 átomos de carbono. Em outras formas de realização, os grupos alcóxi contêm de 1 a 8 átomos de carbono. Ainda em outras formas de realização, os grupos alcóxi contêm de 1 a 6 átomos de carbono, e já em outras formas de realização, os grupos alcóxi contêm de 1 a 3 átomos de carbono.[0065] The term "alkoxy" as used herein, refers to an alkyl group, as defined above, attached to the main carbon atom through an oxygen atom. Unless otherwise specified, alkoxy groups contain 1 to 20 carbon atoms. In some embodiments, alkoxy groups contain 1 to 10 carbon atoms. In other embodiments, alkoxy groups contain 1 to 8 carbon atoms. In still other embodiments, alkoxy groups contain 1 to 6 carbon atoms, and in other embodiments, alkoxy groups contain 1 to 3 carbon atoms.
[0066] Os exemplos de grupos alcóxi incluem, mas não são limitados a, metóxi (MeO, -OCH3), etóxi (EtO, -OCH2CH3), 1-propóxi (n-PrO, n- propóxi, -OCH2CH2CH3), 2-propóxi (i-PrO, i-propóxi, -OCH(CH3)2), 1- butóxi (n-BuO, n-butóxi, -OCH2CH2CH2CH3), 2-metil-1-propóxi (i-BuO, i- butóxi, -OCH2CH(CH3)2), 2-butóxi (s-BuO, s-butóxi, -OCH(CH3)CH2CH3), 2-metil-2-propóxi (t-BuO, t-butóxi, -OC(CH3)3), 1-pentóxi (n-pentóxi, - OCH2CH2CH2CH2CH3), 2-pentóxi (-OCH(CH3)CH2CH2CH3), 3-pentóxi (- OCH(CH2CH3)2), 2-metil-2-butóxi (-OC(CH3)2CH2CH3), 3-metil-2-butóxi (- OCH(CH3)CH(CH3)2), 3-metil-1-butóxi (-OCH2CH2CH(CH3)2), 2-metil-1- butóxi (-OCH2CH(CH3)CH2CH3), e os semelhantes. Os radicais alcóxi são opcionalmente substituídos independentemente com um ou mais substituintes aqui descritos.[0066] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2- propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3 ), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3 )2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (-OCH2CH (CH3)CH2CH3), and the like. Alkoxy radicals are optionally independently substituted with one or more substituents described herein.
[0067] Os termos “haloalquila” e “haloalcóxi” significam alquila, ou alcóxi, como o case pode ser, substituídos com um ou mais átomos de halógeno.[0067] The terms "haloalkyl" and "haloalkoxy" mean alkyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.
[0068] O termo “alquilamino” abrange “N-alquilamino” e “N,N- dialquilamino” onde os grupos amino são independentemente substituídos com um radical de alquila e com dois radicais alquila, respectivamente. Os radicais de alquilamino mais preferidos são os radicais de “alquilamino inferior” tendo 1 ou 2 radicais alquila de 1 a 6 átomos de carbono ligados a um átomo de nitrogênio. Os radicais de alquilamino ainda mais preferidos contêm de 1 a 3 átomos de carbono. Os radicais de alquilamino adequados podem ser mono ou dialquilamino tais como N-metilamino, N-etilamino, N,N-dimetilamino, N,N-dietilamino, e os semelhantes.The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino" where the amino groups are independently substituted with one alkyl radical and two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having 1 or 2 alkyl radicals of 1 to 6 carbon atoms attached to a nitrogen atom. Even more preferred alkylamino radicals contain 1 to 3 carbon atoms. Suitable alkylamino radicals can be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.
[0069] O termo “arilamino” indica grupos amino, que foram substituídos com um ou dois radicais de arila, tais como N-fenilamino. Os radicais de arilamino podem ser substituídos ainda na porção do anel de arila do radical.[0069] The term "arylamino" indicates amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino. Arylamino radicals can be substituted further on the aryl ring portion of the radical.
[0070] O termo “aminoalquila” abrange radicais de alquila lineares ou ramificados tendo de um a cerca de dez átomos de carbono qualquer um dos quais pode ser substituído com um ou mais radicais de amino. Os radicais de aminoalquila mais preferidos são os radicais de “aminoalquila inferior” tendo de um a seis átomos de carbono e um ou mais radicais de amino. Alguns exemplos não limitantes de tais radicais incluem aminometila, aminoetila, aminopropila, aminobutila e aminohexila.The term "aminoalkyl" embraces linear or branched alkyl radicals having from one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Some non-limiting examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
[0071] Os termos “carbociclo”, “carbociclila”, “anel carbocíclico” e “cicloalifático” referem-se a um anel monovalente ou multivalente não aromático, saturado ou parcialmente insaturado tendo de 3 a 12 átomos de carbono como um sistema de anel monocíclico, bicíclico, ou tricíclico. Um sistema de anel bicíclico inclui um biciclila espiro ou um biciclila fundido. Os grupos carbociclila adequados incluem, mas não são limitados a, cicloalquila, cicloalquenila, e cicloalquinila. Outros exemplos não limitantes de grupos carbociclila incluem ciclopropila, ciclobutila, ciclopentila, 1-ciclopent-1- enila, l-ciclopent-2-enila, l-ciclopent-3-enila, ciclohexila, 1-ciclohex-1-enila, l-ciclohex-2-enila, l-ciclohex-3-enila, ciclohexadienila, e os semelhantes.[0071] The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloaliphatic" refer to a non-aromatic, saturated or partially unsaturated monovalent or multivalent ring having from 3 to 12 carbon atoms as a ring system monocyclic, bicyclic, or tricyclic. A bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Other non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1- cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, and the like.
[0072] O termo “cicloalquila” refere-se a um anel saturado monovalente ou multivalente tendo de 3 a 12 átomos de carbono como um sistema de anel monocíclico, bicíclico, ou tricíclico. Um sistema de anel bicíclico inclui um biciclila espiro ou um biciclila fundido. Em algumas formas de realização, um cicloalquila contém de 3 a 10 átomos de carbono. Ainda em outras formas de realização, um cicloalquila contém de 3 a 8 átomos de carbono, e já em outras formas de realização, um cicloalquila contém de 3 a 6 átomos de carbono. Os radicais de cicloalquila são opcionalmente substituídos independentemente com um ou mais substituintes aqui descritos.[0072] The term "cycloalkyl" refers to a saturated monovalent or multivalent ring having from 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. A bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl. In some embodiments, a cycloalkyl contains 3 to 10 carbon atoms. In still other embodiments, a cycloalkyl contains from 3 to 8 carbon atoms, and in other embodiments, a cycloalkyl contains from 3 to 6 carbon atoms. Cycloalkyl radicals are optionally independently substituted with one or more substituents described herein.
[0073] O termo “heterociclo”, “heterociclila” ou “heterocíclico” como aqui usado intercambiavelmente refere-se a um sistema de anel monocíclico, bicíclico, ou tricíclico em que um ou mais membros do anel são independentemente selecionados de heteroátomos e que é completamente saturado ou que contém uma ou mais unidades de insaturação, mas que não é aromático, que tem um ou mais pontos de ligação ao resto da molécula. Um sistema de anel bicíclico inclui um biciclila espiro ou um biciclila fundido, e um dos anéis pode ser um monocarbociclo ou um monoheterociclo. Um ou mais átomos do anel são opcionalmente substituídos independentemente com um ou mais substituintes aqui descritos. Em algumas formas de realização, os grupos “heterociclo”, “heterociclila”, ou “heterocíclico” são um monociclo tendo de 3 a 7 membros do anel (de 2 a 6 átomos de carbono e de 1 a 3 heteroátomos selecionados de N, O, P, e S, em que o S ou P são opcionalmente substituídos com um ou mais oxo para fornecer os grupos SO ou SO2, PO ou PO2). Em outras formas de realização, são um monociclo tendo de 3 a 6 membros do anel (de 2 a 5 átomos de carbono e de 1 a 2 heteroátomos selecionados de N, O, P, e S, em que o S ou P são opcionalmente substituídos com um ou mais oxo para fornecer os grupos SO ou SO2, PO ou PO2) ou um biciclo tendo de 7 a 10 membros do anel (de 4 a 9 átomos de carbono e de 1 a 3 heteroátomos selecionados de N, O, P, e S, em que o S ou P são opcionalmente substituídos com um ou mais oxo para fornecer os grupos SO ou SO2, PO ou PO2).[0073] The term "heterocycle", "heterocyclyl" or "heterocyclic" as used interchangeably herein refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected from heteroatoms and which is either fully saturated or containing one or more unsaturation units, but not aromatic, having one or more points of attachment to the rest of the molecule. A bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl, and one of the rings can be a monocarbocycle or a monoheterocycle. One or more ring atoms are optionally independently substituted with one or more substituents described herein. In some embodiments, the "heterocycle", "heterocyclyl", or "heterocyclic" groups are a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O , P, and S, where the S or P is optionally substituted with one or more oxo to give the groups SO or SO2, PO or PO2). In other embodiments, they are a monocycle having 3 to 6 ring members (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, P, and S, wherein the S or P is optionally substituted with one or more oxo to give the groups SO or SO2, PO or PO2) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P , and S, where the S or P is optionally substituted with one or more oxo to give the groups SO or SO2, PO or PO2).
[0074] O heterociclila pode ser um radical de carbono ou radical de heteroátomo. Os exemplos de anéis heterocíclicos incluem, mas não são limitados a, pirrolidinila, tetraidrofuranila, diidrofuranila, tetraidrotienila, tetraidropiranila, diidropiranila, tetraidrotiopiranila, piperidino, morfolino, tiomorfolino, tioxanila, piperazinila, homopiperazinila, azetidinila, oxetanila, tietanila, homopiperidinila, oxepanila, tiepanila, oxazepinila, diazepinila, tiazepinila, 2-pirrolinila, 3-pirrolinila, indolinila, 2H-piranila, 4H-piranila, dioxanila, 1,3-dioxolanila, pirazolinila, ditianila, ditiolanila, diidropiranila, diidrotienila, pirazolidinila, imidazolinila, imidazolidinila, 1,2,3,4-tetraidro- isoquinolinila. Alguns exemplos não limitantes de um grupo heterocíclico em que 2 átomos do anel de carbono são substituídos com porções oxo (=O) são pirimidindionila e 1, 1-dioxo-tiomorfolinila.[0074] The heterocyclyl can be a carbon radical or a heteroatom radical. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, dihydrofuranyl, homopiperazinyl, piperazinyl, thiazinyyl, thiazinyyl, o , oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, 1-imidazolidinyl, imidazolidinyl ,2,3,4-tetrahydro-isoquinolinyl. Some non-limiting examples of a heterocyclic group in which 2 carbon ring atoms are replaced with oxo (=O) moieties are pyrimidindionyl and 1,1-dioxo-thiomorpholinyl.
[0075] O termo “heteroátomo” significa um ou mais de oxigênio, enxofre, nitrogênio, fósforo, ou silício, incluindo qualquer forma oxidada de nitrogênio, enxofre, ou fósforo; a forma quaternizada de qualquer nitrogênio básico; ou um nitrogênio substituível de um anel heterocíclico, por exemplo N (como em 3,4-diidro-2H-pirrolila), NH (como em pirrolidinila) ou NR (como em pirrolidinila N-substituído).[0075] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).
[0076] O termo “halógeno” refere-se a flúor (F), cloro (Cl), bromo (Br) ou iodo (I).[0076] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
[0077] O termo “H” indica um átomo de hidrogênio único. Este radical pode ser ligado, por exemplo, a um átomo de oxigênio para formar um radical hidroxila.[0077] The term "H" indicates a single hydrogen atom. This radical can be attached, for example, to an oxygen atom to form a hydroxyl radical.
[0078] O termo “D” ou “2H” indica um átomo de deutério único. Um deste radical pode ser ligado, por exemplo, a um grupo metila para formar um grupo metila mono-deuterado (-CDH2), dois de átomos de deutério podem ser ligados a um grupo metila para formar um metila di-deuterado (-CD2H), e três de átomos de deutério podem ser ligados a um grupo metila para formar um grupo metila tri-deuterado (-CD3).[0078] The term “D” or “2H” indicates a single deuterium atom. One of this radical can be attached, for example, to a methyl group to form a mono-deuterated methyl group (-CDH2), two of deuterium atoms can be attached to a methyl group to form a di-deuterated methyl (-CD2H) , and three of deuterium atoms can be attached to a methyl group to form a tri-deuterated methyl group (-CD3).
[0079] O termo “N3” indica uma porção de azida. Este radical pode ser ligado, por exemplo, a um grupo metila para formar azidometano (metil azida, MeN3); ou ligado a um grupo fenila para formar fenil azida (PhN3).[0079] The term "N3" indicates an azide moiety. This radical can be attached, for example, to a methyl group to form azidomethane (methyl azide, MeN3); or attached to a phenyl group to form phenyl azide (PhN3).
[0080] O termo “arila” usado sozinho ou como parte de uma porção maior como em “aralquila”, “aralcóxi” ou “ariloxialquila” refere-se a sistemas de anel carbocíclico monocíclicos, bicíclicos, e tricíclicos tendo um total de 6 a 14 membros do anel, preferivelmente, de 6 a 12 membros do anel, e mais preferivelmente de 6 a 10 membros do anel, em que pelo menos um anel no sistema é aromático, em que cada anel no sistema contém de 3 a 7 membros do anel e que tem um ou mais pontos de ligação ao resto da molécula. O termo “arilc” pode ser usado intercambiavelmente com os termos “anel de arila” ou “aromático”. Alguns exemplos não limitantes de anéis de arila incluiriam fenila, naftila, e antraceno. Os radicais de arila são opcionalmente substituídos independentemente com um ou mais substituintes aqui descritos.The term "aryl" used alone or as part of a larger portion as in "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, preferably 6 to 12 ring members, and more preferably 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains from 3 to 7 ring members. ring and which has one or more points of attachment to the rest of the molecule. The term "arilc" may be used interchangeably with the terms "aryla ring" or "aromatic". Some non-limiting examples of aryl rings would include phenyl, naphthyl, and anthracene. Aryl radicals are optionally independently substituted with one or more substituents described herein.
[0081] O termo “heteroarknc” usado sozinho ou como parte de uma porção maior como em “heteroaralquknc” ou “heteroarilalcóxi” refere-se a sistemas de anel monocíclicos, bicíclicos, e tricíclicos tendo um total de 5 a 14 membros do anel, preferivelmente, de 5 a 12 membros do anel, e mais preferivelmente de 5 a 10 membros do anel, em que pelo menos um anel no sistema é aromático, pelo menos um anel no sistema contém um ou mais heteroátomos, em que cada anel no sistema contém de 5 a 7 membros do anel e que tem um ou mais pontos de ligação ao resto da molécula. Em algumas formas de realização, um heteroarila de 5 a 10 membros compreende 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N. O termo “heteroarüc” pode ser usado intercambiavelmente com o termo “anel de heteroarila” ou o termo “heteroaromático”. Os radicais de heteroarila são opcionalmente substituídos independentemente com um ou mais substituintes aqui descritos.[0081] The term "heteroarylalkoxy" used alone or as part of a larger portion as in "heteroarylalkoxy" or "heteroarylalkoxy" refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, preferably, from 5 to 12 ring members, and more preferably from 5 to 10 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 5 to 7 ring members and has one or more points of attachment to the rest of the molecule. In some embodiments, a 5- to 10-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. The term "heteroarüc" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Heteroaryl radicals are optionally independently substituted with one or more substituents described herein.
[0082] Outros exemplos não limitantes de anéis de heteroarila incluem os seguintes monociclos: 2-furanila, 3-furanila, N-imidazolila, 2- imidazolila, 4-imidazolila, 5-imidazolila, 3-isoxazolila, 4-isoxazolila, 5- isoxazolila, 2-oxazolila, 4-oxazolila, 5-oxazolila, N-pirrolila, 2-pirrolila, 3- pirrolila, 2-piridila, 3-piridila, 4-piridila, 2-pirimidinila, 4-pirimidinila, 5- pirimidinila, piridazinila (por exemplo, 3-piridazinila), 2-tiazolila, 4-tiazolila, 5-tiazolila, tetrazolila (por exemplo, 5-tetrazolila), triazolila (por exemplo, 2- triazolila e 5-triazolila), 2-tienila, 3-tienila, pirazolila (por exemplo, 2- pirazolila), isotiazolila, 1,2,3-oxadiazolila, 1,2,5-oxadiazolila, 1,2,4- oxadiazolila, 1,2,3-triazolila, 1,2,3-tiadiazolila, 1,3,4-tiadiazolila, 1,2,5- tiadiazolila, pirazinila, 1,3,5-triazinila, e os seguintes biciclos: benzimidazolila, benzofurila, benzotiofenila, indolila (por exemplo, 2- indolila), purinila, quinolinila (por exemplo, 2-quinolinila, 3-quinolinila, 4- quinolinila), e isoquinolinila (por exemplo, 1-isoquinolinila, 3-isoquinolinila ou 4-isoquinolinila).[0082] Other non-limiting examples of heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5-tetrazolyl), triazolyl (eg 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1, 2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (eg 2- indolyl), purinyl, quinolinyl (eg, 2-quinolinyl, 3-quinolinyl, 4-quino linyl), and isoquinolinyl (for example, 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).
[0083] Os termos “bicíclico fundido”, “cíclico fundido”, “biciclila fundido” e “ciclila fundido” que são usados intercambiavelmente referem-se a um sistema de anel ligado em ponte monovalente ou multivalente saturado, que refere-se a um sistema de anel bicíclico que não é aromático. Um tal sistema pode conter insaturação isolada ou conjugada, mas não anéis aromáticos ou heteroaromáticos na sua estrutura de núcleo (mas pode ter substituição aromático no mesmo).[0083] The terms "fused bicyclic", "fused cyclic", "fused bicyclyl" and "fused cyclyl" that are used interchangeably refer to a saturated monovalent or multivalent bridged ring system, which refers to a bicyclic ring system that is not aromatic. Such a system may contain isolated or conjugated unsaturation, but no aromatic or heteroaromatic rings in its core structure (but may have aromatic substitution thereon).
[0084] Os termos “espirociclknc”, “espirocíclico”, “espiro biciclknc” ou “espiro bicíclico” são usados intercambiavelmente e referem-se a um sistema de anel monovalente ou multivalente em que um anel que se origina de um carbono anelar particular de um outro anel. Por exemplo, como representado abaixo na Estrutura a, um sistema de anel ligado em ponte saturado (anel B e BÓ) é chamado como “bicíclico fundido”, ao passo que o anel A e anel B compartilham um átomo entre os dois sistemas de anel saturado, que se chama como um “espirociclknc” ou “espiro biciclinc”. Cada anel cíclico em um biciclila fundido ou um espiro biciclila pode ser um carbociclila ou um heterociclila. The terms "spirocycline", "spirocyclic", "spiro bicyclic" or "spiro bicyclic" are used interchangeably and refer to a monovalent or multivalent ring system in which a ring originates from a particular ring carbon of another ring. For example, as depicted below in Structure a, a saturated bridged ring system (ring B and BÓ) is referred to as a "fused bicyclic", whereas ring A and ring B share an atom between the two ring systems. saturated, which is called as a "spirocycline" or "spiro bicyclinc". Each cyclic ring in a fused bicyclyl or a bicyclyl spiro can be a carbocyclyl or a heterocyclyl.
[0085] O termo “insaturado” como aqui usado, significa que uma porção tem uma ou mais unidades de insaturação.[0085] The term "unsaturated" as used herein means that a portion has one or more units of unsaturation.
[0086] O termo “compreendendo” é intencionado ser ilimitado, incluindo o componente indicado mas não excluindo outros elementos.[0086] The term “comprising” is intended to be unlimited, including the indicated component but not excluding other elements.
[0087] O termo “pró-medicamento” como aqui usado, representa um composto que é transformado in vivo em um composto da fórmula (I). Uma tal transformação pode ser afetada, por exemplo, pela hidrólise no sangue ou transformação enzimática da forma de pró-medicamento para a forma precursora no sangue ou tecido. Os pró-medicamentos dos compostos aqui divulgados podem ser, por exemplo, ésteres. Os ésteres que podem ser utilizados como pró-medicamentos na presente invenção são ésteres fenílicos, ésteres alifáticos (C1-C24), ésteres aciloximetílicos, carbonatos, carbamatos, e ésteres de aminoácido. Por exemplo, um composto aqui divulgado que contém um grupo OH pode ser acilado nesta posição na sua forma de pró- medicamento. Outras formas de pró-medicamento incluem fosfatos, tais como, por exemplo aqueles fosfatos que resultam da fosfonação de um grupo OH no composto precursor. Um debate completo de pró-medicamentos é fornecido em T. Higuchi e V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 da A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Pro-Drugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, e S. J. Hecker et al, Pro-Drugs of Fosfates and Fosfonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, cada um dos quais é aqui incorporado por referência.[0087] The term "pro-drug" as used herein, represents a compound that is transformed in vivo into a compound of formula (I). Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation from the prodrug form to the precursor form in blood or tissue. Prodrugs of the compounds disclosed herein can be, for example, esters. Esters that can be used as prodrugs in the present invention are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein that contains an OH group can be acylated at this position in its prodrug form. Other forms of prodrug include phosphates, such as, for example, those phosphates which result from the phosphonation of an OH group on the parent compound. A full discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Pro-Drugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Pro-Drugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, each of which is incorporated herein by reference.
[0088] Um “metabólito” é um produto produzido através do metabolismo no corpo de um composto especificado ou sal do mesmo. Os metabólitos de um composto podem ser identificados usando técnicas de rotina conhecidas na técnica e as suas atividades determinadas usando testes tais como aqueles aqui descritos. Tais produtos podem resultar por exemplo da oxidação, redução, hidrólise, amidação, desamidação, esterificação, desesterificação, clivagem enzimática, e os semelhantes, do composto administrado. Consequentemente, a invenção inclui metabólitos dos compostos aqui divulgados, incluindo compostos produzidos por um processo compreendendo contatar um composto desta invenção com um mamífero por um período de tempo suficiente para produzir um produto metabólico do mesmo.[0088] A "metabolite" is a product produced through the metabolism in the body of a specified compound or salt thereof. Metabolites of a compound can be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of the compounds disclosed herein, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
[0089] Um “sal farmaceuticamente aceitável” como aqui usado, refere-se a sais orgânicos ou inorgânicos de um composto aqui divulgado. Os sais farmaceuticamente aceitáveis são bem conhecidos na técnica. Por exemplo, S. M. Berge et al., descrevem sais farmaceuticamente aceitáveis em detalhes em J. Pharmaceutical Sciences 1977, 66, 1-19, que é aqui incorporada por referência. Os exemplos de sais farmaceuticamente aceitáveis, não tóxicos incluem, mas não são limitados a, sais de um grupo amino formado com ácidos inorgânicos tais como ácido clorídrico, ácido bromídrico, ácido fosfórico, ácido sulfúrico e ácido perclórico ou com ácidos orgânicos tais como ácido acético, ácido oxálico, ácido maléico, ácido tartárico, ácido cítrico, ácido succínico ou ácido malônico ou usando-se outros métodos usados na técnica tais como troca de íon. Outros sais farmaceuticamente aceitáveis incluem os sais de adipato, alginato, ascorbato, aspartato, benzenossulfonato, benzoato, bissulfato, borato, butirato, canforato, canforsulfonato, citrato, ciclopentanopropionato, digluconato, dodecilsulfato, etanossulfonato, formiato, fumarato, glicoheptonato, glicerofosfato, gliconato, hemissulfato, heptanoato, hexanoato, iodidreto, 2-hidróxi-etanossulfonato, lactobionato, lactato, laurato, lauril sulfato, malato, maleato, malonato, metanossulfonato, 2-naftalenossulfonato, nicotinato, nitrato, oleato, oxalato, palmitato, pamoato, pectinato, persulfato, 3-fenilpropionato, fosfato, picrato, pivalato, propionato, estearato, succinato, sulfato, tartarato, tiocianato, p- toluenossulfonato, undecanoato, valerato, e os semelhantes. Sais derivados de bases apropriadas incluem os sais de metal alcalino, metal alcalino terroso, amônio e N+(alquila C1-4)4. Esta invenção também prevê a quaternização de qualquer um dos grupos contendo nitrogênio básico dos compostos aqui divulgados. Produtos solúveis ou dispersáveis em água ou óleo podem ser obtidos pela tal quaternização. Os sais de metal alcalino ou alcalino terroso representativos incluem sódio, lítio, potássio, cálcio, magnésio, e os semelhantes. Outros sais farmaceuticamente aceitáveis incluem, quando apropriado, cátions não tóxicos de amônio, amônio quaternário, e amina formados usando contraíons tais como haleto, hidróxido, carboxilato, sulfato, fosfato, nitrato, C1-8 sulfonato e aril sulfonato.[0089] A "pharmaceutically acceptable salt" as used herein, refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66, 1-19, which is incorporated herein by reference. Examples of non-toxic, pharmaceutically acceptable salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glycoheptonate, camphorate salts hemisulphate, heptanoate, hexanoate, iodide, 2-hydroxyethanesulphonate, lactobionate, lactate, laurate, lauryl sulphate, malate, maleate, malonate, methanesulphonate, 2-naphthalenesulphonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, persulphate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4 salts. This invention also envisions the quaternization of any of the basic nitrogen containing groups of the compounds disclosed herein. Soluble or dispersible products in water or oil can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C1-8 sulfonate, and aryl sulfonate.
[0090] Um “solvato” refere-se a uma associação ou complexo de uma ou mais moléculas de solvente e um composto aqui divulgado. Os exemplos de solventes que formam solvatos incluem, mas não são limitados a, água, isopropanol, etanol, metanol, DMSO, acetato de etila, ácido acético e etanolamina. O termo “hidrato” refere-se ao complexo onde a molécula de solvente é água.[0090] A "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.
[0091] Como aqui usado, o termo “carregador farmaceuticamente aceitável” inclui qualquer um e todos solventes, meios de dispersão, revestimentos, tensoativos, antioxidantes, preservantes (por exemplo, agentes antibacterianos, agentes antifúngicos), agentes isotônicos, agentes retardantes de absorção, sais, preservantes, estabilizantes de medicamento, aglutinantes, excipientes, agentes de desintegração, lubrificantes, agentes adoçantes, agentes flavorizantes, corantes, e os semelhantes e combinações dos mesmos, como seriam conhecidos por aqueles habilitados na técnica (ver, por exemplo, RemingtonÓs Pharmaceutical Sciences, 18a Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceto na medida em que qualquer carregador convencional seja incompatível com o ingrediente ativo, o seu uso nas composições terapêuticas ou farmacêuticas é considerado.[0091] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents , salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, colorants, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except to the extent that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is considered.
[0092] O termo “uma quantidade terapeuticamente eficaz” de um composto aqui divulgado refere-se a uma quantidade do composto aqui divulgado que evocará a resposta biológica ou médica de um indivíduo, por exemplo, redução ou inibição de uma atividade de enzima ou uma proteína, ou melhorar os sintomas, aliviar as condições, diminuir ou retardar a progressão da doença, ou prevenir uma doença, etc. Em uma forma de realização não limitante, o termo “uma quantidade terapeuticamente eficaz” refere-se à quantidade do composto aqui divulgado que, quando administrada a um indivíduo, é eficaz para (1) pelo menos parcialmente aliviar, inibir, prevenir e/ou melhorar uma condição, ou um distúrbio ou uma doença (i) mediada pela PI3K ou (ii) associada com a atividade de PI3K, ou (iii) caracterizado pela atividade (normal ou anormal) de PI3K ou (2) reduzir ou inibir a atividade de PI3K ou (3) reduzir ou inibir a expressão de PI3K. Em uma outra forma de realização não limitante, o termo “uma quantidade terapeuticamente eficaz” refere-se à quantidade do composto aqui divulgado que, quando administrado a uma célula, ou um tecido, ou um material biológico não celular, ou um meio, é eficaz para pelo menos parcialmente reduzir ou inibir a atividade de PI3K; ou pelo menos parcialmente reduzir ou inibir a expressão de PI3K. O significado do termo “uma quantidade terapeuticamente eficaz” como ilustrado na forma de realização acima para PI3K também se aplica pelo mesmo significado a qualquer outra das proteínas/peptídeos/enzimas.The term "a therapeutically effective amount" of a compound disclosed herein refers to an amount of the compound disclosed herein that will evoke an individual's biological or medical response, e.g., reduction or inhibition of an enzyme activity or a protein, or ameliorating symptoms, alleviating conditions, slowing or slowing disease progression, or preventing a disease, etc. In a non-limiting embodiment, the term "a therapeutically effective amount" refers to that amount of the compound disclosed herein that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorating a condition, or a disorder or a disease (i) mediated by PI3K or (ii) associated with PI3K activity, or (iii) characterized by (normal or abnormal) PI3K activity, or (2) reducing or inhibiting the activity of PI3K or (3) reduce or inhibit PI3K expression. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to that amount of the compound disclosed herein that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit PI3K activity; or at least partially reduce or inhibit PI3K expression. The meaning of the term "a therapeutically effective amount" as illustrated in the above embodiment for PI3K also applies by the same meaning to any other of the proteins/peptides/enzymes.
[0093] Como aqui usados, os termos “tratar”, “tratando” ou “tratamento” de qualquer doença ou distúrbio referem-se em uma forma de realização, à melhora da doença ou distúrbio (isto é, diminuição ou parada ou redução do desenvolvimento da doença ou pelo menos um dos sintomas clínicos da mesma). Em uma outra forma de realização “tratar”, “tratando” ou “tratamento” referem-se ao alívio ou melhora de pelo menos um parâmetro físico incluindo aqueles que podem não ser discerníveis pelo paciente. Ainda em uma outra forma de realização, “tratar”, “tratando” ou “tratamento” referem-se à modulação da doença ou distúrbio, física, (por exemplo, estabilização de um sintoma discernível), fisiologicamente, (por exemplo, estabilização de um parâmetro físico), ou ambos. já em uma outra forma de realização, “tratar”, “tratando” ou “tratamento” referem-se à prevenção ou retardo do início ou desenvolvimento ou progressão da doença ou distúrbio.[0093] As used herein, the terms "treating", "treating" or "treatment" of any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., decreasing or stopping or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment "treating", "treating" or "treatment" refers to the alleviation or improvement of at least one physical parameter including those that may not be discernible by the patient. In yet another embodiment, "treating", "treating" or "treatment" refers to the modulation of the disease or disorder, physically (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. in another embodiment, "treating", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
[0094] Os termos “grupo de proteção” ou “PG” referem-se a um substituinte que é habitualmente utilizado para bloquear ou proteger uma funcionalidade particular enquanto reage com outros grupos funcionais no composto. Por exemplo, um “grupo de proteção de amino” é um substituinte ligado a um grupo amino que bloqueia ou protege a funcionalidade amino no composto. Os grupos de proteção de amino adequados incluem acetila, trifluoroacetila, t-butoxicarbonila (BOC, Boc), benziloxicarbonila (CBZ, Cbz) e 9-fluorenilmetilenoxicarbonila (Fmoc). Similarmente, um “grupo de proteção de hidróxi” refere-se a um substituinte de um grupo hidróxi que bloqueia ou protege a funcionalidade hidróxi. Os grupos de proteção adequados incluem acetila e silila. Um “grupo de proteção de carbóxi” refere- se a um substituinte do grupo carbóxi que bloqueia ou protege a funcionalidade de carbóxi. Os grupos de proteção de carbóxi comuns incluem -CH2CH2SO2Ph, cianoetila, 2-(trimetilsilil)etila, 2-(trimetilsilil)etóxi-metila, 2-(p-toluenossulfonil)etila, 2-(p-nitrofenilsulfenil)-etila, 2-(difenilfosfino)- etila, nitroetila e os semelhantes. Para uma descrição geral de grupos de proteção e seu uso, ver T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Nova Iorque, 1991 e P. J. Kocienski, Protecting Groups, Tieme, Stuttgart, 2005.The terms "protecting group" or "PG" refer to a substituent that is commonly used to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality on the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy protecting group" refers to a substituent on the carboxy group that blocks or protects the carboxy functionality. Common carboxy protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxy-methyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)-ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and P.J. Kocienski, Protecting Groups, Tieme, Stuttgart, 2005.
[0095] São aqui fornecidos compostos aromáticos, sais, e formulações farmacêuticas dos mesmos, que são potencialmente úteis no tratamento de doenças, condições e distúrbios modulados pelas proteína cinases, especialmente PI3K e mTOR. Mais especificamente, a presente invenção fornece um composto da Fórmula (I): Provided herein are aromatic compounds, salts, and pharmaceutical formulations thereof, which are potentially useful in the treatment of diseases, conditions, and disorders modulated by protein kinases, especially PI3K and mTOR. More specifically, the present invention provides a compound of Formula (I):
[0096] ou um estereoisômero, um isômero geométrico, um tautômero, um N-óxido, um solvato, um metabólito, um sal farmacêutico ou um pró- medicamento do mesmo, em que cada um de Y, Z, R1, W1, W2 e W3 é como aqui definido.[0096] or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutical salt or a prodrug thereof, wherein each of Y, Z, R1, W1, W2 and W3 is as defined herein.
[0097] Em certas formas de realização, cada um de W1, W2 e W3 é independentemente N ou CRc;[0097] In certain embodiments, each of W1, W2 and W3 is independently N or CRc;
[0098] Z È D, CN, N3 ou;[0098] Z È D, CN, N3 or ;
[0099] X È H, D, alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), -alquileno (C1-C4)- heterociclila (C3-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), -alquileno (C1- C4)-heterociclila (C3-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1-C6), alquenila (C2-C6), alquinila (C2-C6), -alquileno (C1-C4)-CN, -alquileno (C1-C4)-ORa, -alquileno (C1-C4)-NRaRb, arila (C6-C10) e heteroarila de 5 a 10 membros;[0099] X È H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene(C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C6) C4)- heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, where each is (C1-alkyl) C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3-C6), aryl (C6 -C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb , alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6), alkynyl (C2-C6), -alkylene (C1-C4)-CN, -alkylene (C1-C4)-ORa, - (C1-C4)alkylene-NRaRb, (C6-C10) aryl, and 5- to 10-membered heteroaryl;
[00100] Y é alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), -alquileno (C1-C4)-heterociclila (C3C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3-C6), - alquileno (C1-C4)-heterociclila (C3-C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1C6), alquenila (C2-C6), alquinila (C2-C6), -alquileno (C1-C4)-CN, -alquileno (C1-C4)-ORa, -alquileno (C1-C4)-NRaRb, arila (C6-C10) e heteroarila de 5 a 10 membros;[00100] Y is alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), -alkylene (C1-C4)-heterocyclyl (C3C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, in that each of alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3-C6), - alkylene (C1-C4)-heterocyclyl ( C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F , Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1C6), alkenyl (C2-C6), alkynyl (C2-C6), - (C 1 -C 4 )alkylene-CN, -(C 1 -C 4 )alkylene-ORa, -(C 1 -C 4 )alkylene-NRaRb, (C 6 -C 10 ) aryl, and 5- to 10-membered heteroaryl;
[00101] R1 é H, D, Cl, ORa, NRaRb, alífático (C1-C6) ou cicloalquila (C3-C6), em que cada um do alífático (C1-C6) e cicloalquila (C3-C6) é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, CN, N3, ORa, SRa e NRaRb, contanto que quando cada um de W1, W2 e W3 é CH, R1 não seja H ou NH2;[00101] R1 is H, D, Cl, ORa, NRaRb, aliphatic (C1-C6) or cycloalkyl (C3-C6), wherein each of the aliphatic (C1-C6) and cycloalkyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, ORa, SRa and NRaRb, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2;
[00102] cada Ra e Rb é independentemente H, alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), arila (C6-C10), heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, -alquileno (C1-C4)-arila (C6-C10) ou -alquileno (C1- C4)-(heteroarila de 5 a 10 membros); ou quando Ra e Rb são ligados ao mesmo átomo de nitrogênio, Ra e Rb, juntos com o átomo de nitrogênio ao qual eles estão ligados, opcionalmente formam um anel heterocíclico de 3 a 8 membros substituído ou não substituído, em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, CN, N3, OH, NH2, alcóxi (C1C6), e alquila (C1-C6)amino; e[00102] each Ra and Rb is independently H, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, -(C 1 -C 4 )alkylene- (C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(5- to 10-membered heteroaryl); or when Ra and Rb are attached to the same nitrogen atom, Ra and Rb, together with the nitrogen atom to which they are attached, optionally form a substituted or unsubstituted 3- to 8-membered heterocyclic ring, wherein each of the alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10), and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, alkoxy(C1C6), and alkyl(C1-C6)amino; and
[00103] cada Rc é independentemente H, D, F, Cl, Br, I, N3, CN, OH, NH2, alquila (C1-C6), alcóxi (C1-C6), alquila (C1-C6) amino, cicloalquila (C3C6), heterociclila (C3-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, em que cada um do alquila (C1-C6), alcóxi (C1-C6), alquila (C1-C6) amino, cicloalquila (C3-C6), heterociclila (C3-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, CN, N3, OH, NH2, alquila (C1C6), cicloalquila (C3-C6), haloalquila (C1-C6), alcóxi (C1-C6) e alquila (C1-C6) amino.[00103] each Rc is independently H, D, F, Cl, Br, I, N3, CN, OH, NH2, alkyl (C1-C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3C6), heterocyclyl (C3-C6), aryl (C6-C10), or 5- to 10-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, where each of (C1) alkyl -C6), alkoxy (C1-C6), alkyl (C1-C6) amino, cycloalkyl (C3-C6), heterocyclyl (C3-C6), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N3, OH, NH2, alkyl (C1C6), cycloalkyl (C3-C6), haloalkyl (C1-C6), alkoxy (C1-C6) and (C1-C6) alkylamino.
[00104] Em uma outra forma de realização, cada um de W1 e W2 é independentemente N ou CRc, W3 é CRc.[00104] In another embodiment, each of W1 and W2 is independently N or CRc, W3 is CRc.
[00105] Em uma outra forma de realização, Z é CN, N3 ou x.[00105] In another embodiment, Z is CN, N3 or x.
[00106] Em uma outra forma de realização, X é H, D, alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)-cicloalquila (C3C6) ou -alquileno (C1-C4)-heterociclila (C3-C6), em que cada um do alquila (C1-C6), cicloalquila (C3-C6), heterociclila (C3-C6), -alquileno (C1-C4)- cicloalquila (C3-C6) e -alquileno (C1-C4)-heterociclila (C3-C6) é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1-C6), alquenila (C2-C6) e alquinila (C2-C6).[00106] In another embodiment, X is H, D, alkyl (C1-C6), cycloalkyl (C3-C6), heterocyclyl (C3-C6), -alkylene (C1-C4)-cycloalkyl (C3C6) or -(C1-C4)alkylene-(C3-C6)heterocyclyl, wherein each of (C1-C6)alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclyl, (C1-C4)alkylene-cycloalkyl (C3-C6) and -(C1-C4)alkylene-heterocyclyl (C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa , NRaRb, -C(=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkenyl (C2-C6) and alkynyl (C2-C6).
[00107] Em uma outra forma de realização, Y é alquila (C1-C6), cicloalquila (C3-C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) ou heteroarila de 5 a 10 membros compreendendo 1, 2, 3 ou 4 heteroátomos independentemente selecionados de O, S e N, em que cada um do alquila (C1C6), cicloalquila (C3-C6), alquenila (C2-C6), alquinila (C2-C6), arila (C6-C10) e heteroarila de 5 a 10 membros é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C(=O)NRaRb, alquila (C1-C6), haloalquila (C1-C6), alquinila (C2C6), arila (C6-C10) e heteroarila de 5 a 10 membros.[00107] In another embodiment, Y is alkyl (C1-C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6), aryl (C6-C10) or heteroaryl of 5 to 10 members comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of alkyl (C1C6), cycloalkyl (C3-C6), alkenyl (C2-C6), alkynyl (C2-C6 ), aryl (C6-C10) and 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N3, ORa, SRa, NRaRb, -C (=O)NRaRb, alkyl (C1-C6), haloalkyl (C1-C6), alkynyl (C2C6), aryl (C6-C10) and 5- to 10-membered heteroaryl.
[00108] Em uma outra forma de realização, R1 é H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3, OCH2CH3, NH2, NHCH3 ou N(CH3)2, contanto que quando cada um de W1, W2 e W3 é CH, R1 não é H ou NH2.[00108] In another embodiment, R1 is H, D, Cl, CH3, CH2CH3, CF3, CH2CF3, OCH3, OCH2CH3, NH2, NHCH3 or N(CH3)2, provided that when each of W1, W2 and W3 is CH, R1 is not H or NH2.
[00109] Em uma outra forma de realização, cada Rc é independentemente H, D, F, Cl, N3, CN, NH2, alquila (C1-C3), alcóxi (C1-C3), alquila (C1-C3) amino, cicloalquila (C3-C6) ou heterociclila (C3-C6), em que cada um do alquila (C1-C3), alcóxi (C1-C3), alquila (C1-C3) amino, cicloalquila (C3-C6) e heterociclila (C3-C6) é opcionalmente substituído com 1, 2, 3 ou 4 substituintes independentemente selecionados de D, F, CN, N3, OH, NH2, alquila (C1-C3), cicloalquila (C3-C6) e haloalquila (C1-C3).[00109] In another embodiment, each Rc is independently H, D, F, Cl, N3, CN, NH2, alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) or heterocyclyl (C3-C6), wherein each of alkyl (C1-C3), alkoxy (C1-C3), alkyl (C1-C3) amino, cycloalkyl (C3-C6) and heterocyclyl ( C3-C6) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CN, N3, OH, NH2, alkyl (C1-C3), cycloalkyl (C3-C6) and haloalkyl (C1-C3 ).
[00110] Alguns exemplos não limitantes dos compostos aqui divulgados são mostrados nos seguintes: Tabela 1 [00110] Some non-limiting examples of the compounds disclosed herein are shown in the following: Table 1
[00111] A presente invenção também compreende o uso de um composto aqui divulgado, ou sal farmaceuticamente aceitável do mesmo, na fabricação de um medicamento para o tratamento aguda ou cronicamente de um estado de doença hiperproliferativa e/ou um estado de doença mediada pela angiogênese, incluindo aquelas anteriormente descritas. Os compostos aqui divulgados são úteis na fabricação de um medicamento anticâncer. Os compostos aqui divulgados também são úteis na fabricação de um medicamento para atenuar ou prevenir distúrbios através da inibição das proteína cinases. A presente invenção compreende uma composição farmacêutica compreendendo uma quantidade terapeuticamente eficaz de um composto da Fórmula (I) em associação com pelo menos um carregador, adjuvante ou diluente farmaceuticamente aceitáveis.[00111] The present invention also comprises the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the acutely or chronically treatment of a hyperproliferative disease state and/or an angiogenesis-mediated disease state , including those described above. The compounds disclosed herein are useful in the manufacture of an anti-cancer drug. The compounds disclosed herein are also useful in the manufacture of a medicament for alleviating or preventing disorders through inhibition of protein kinases. The present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
[00112] A presente invenção também compreende um método de tratar distúrbios relacionados com a hiperproliferação e angiogênese em um indivíduo tendo ou suscetível a tal distúrbio, o método compreendendo tratar o indivíduo com uma quantidade terapeuticamente eficaz de um composto da Fórmula (I).The present invention also comprises a method of treating disorders related to hyperproliferation and angiogenesis in a subject having or susceptible to such a disorder, the method comprising treating the subject with a therapeutically effective amount of a compound of Formula (I).
[00113] A menos que de outro modo estabelecido, todos os estereoisômeros, isômeros geométricos, tautômeros, solvatos, metabólitos, sais, e pró-medicamentos farmaceuticamente aceitáveis dos compostos aqui divulgados estão dentro do escopo da invenção.[00113] Unless otherwise stated, all pharmaceutically acceptable stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts, and prodrugs of the compounds disclosed herein are within the scope of the invention.
[00114] Em certas formas de realização, o sal é um sal farmaceuticamente aceitável. A frase “farmaceuticamente aceitável” indica que a substância ou composição deve ser química e/ou toxicologicamente compatível, com os outros ingredientes compreendendo uma formulação, e/ou com o mamífero sendo tratado com o mesmo.In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and/or toxicologically compatible, with the other ingredients comprising a formulation, and/or with the mammal being treated therewith.
[00115] Os compostos aqui divulgados também incluem sais de tais compostos que não são necessariamente sais farmaceuticamente aceitáveis, e que podem ser úteis como intermediários para preparar e/ou purificar compostos da Fórmula (I) e/ou para separar enantiômeros dos compostos da Fórmula (I).The compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I).
[00116] Os sais de adição de ácido farmaceuticamente aceitáveis podem ser formados com ácidos inorgânicos e ácidos orgânicos, por exemplo, sais de acetato, aspartato, benzoato, besilato, brometo/bromidreto, bicarbonato/ carbonato, bissulfato/sulfato, canforsulfonato, cloreto/cloridreto, clorteofilonato, citrato, etandissulfonato, fumarato, gluceptato, gluconato, glucuronato, hipurato, iodidreto/iodo, isetionato, lactato, lactobionato, laurilsulfato, malato, maleato, malonato, mandelato, mesilato, metilsulfato, naftoato, napsilato, nicotinato, nitrato, octadecanoato, oleato, oxalato, palmitato, pamoato, fosfato/hidrogeno fosfato/diidrogeno fosfato, poligalacturonato, propionato, estearato, succinato, subsalicilato, tartarato, tosilato e trifluoroacetato.[00116] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, for example, acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/ hydrochloride, chlortheophylonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, iodide/iodine, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, nitrate, naphthoate octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate.
[00117] Os ácidos inorgânicos a partir dos quais sais podem ser derivados incluem, por exemplo, ácido clorídrico, ácido bromídrico, ácido sulfúrico, ácido nítrico, ácido fosfórico, e os semelhantes.Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
[00118] Os ácidos orgânicos a partir dos quais sais podem ser derivados incluem, por exemplo, ácido acético, ácido propiônico, ácido glicólico, ácido oxálico, ácido maléico, ácido malônico, ácido succínico, ácido fumárico, ácido tartárico, ácido cítrico, ácido benzóico, ácido mandélico, ácido metanossulfônico, ácido etanossulfônico, ácido toluenossulfônico, ácido sulfossalicílico, e os semelhantes.[00118] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, acid benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
[00119] Os sais de adição de base farmaceuticamente aceitáveis podem ser formados com bases inorgânicas e orgânicas.[00119] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
[00120] As bases inorgânicas a partir dos quais sais podem ser derivados incluem, por exemplo, sais de amônio e metais das colunas I a XII da tabela periódica. Em certas formas de realização, os sais são derivados de sódio, potássio, amônio, cálcio, magnésio, ferro, prata, zinco, e cobre; os sais particularmente adequados incluem os sais de amônio, potássio, sódio, cálcio e magnésio.[00120] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium and magnesium salts.
[00121] As bases orgânicas a partir das quais sais podem ser derivados incluem, por exemplo, aminas primárias, secundárias, e terciárias, aminas substituídas incluindo as aminas substituídas que ocorrem naturalmente, aminas cíclicas, resinas básicas de troca de íon e os semelhantes. Certas aminas orgânicas incluem isopropilamina, benzatina, colinato, dietanolamina, dietilamina, lisina, meglumina, piperazina e trometamina.Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
[00122] Os sais farmaceuticamente aceitáveis da presente invenção podem ser sintetizados a partir de uma porção básica ou ácida, pelos métodos químicos convencionais. No geral, tais sais podem ser preparados reagindo-se as formas de ácido livre destes compostos com uma quantidade estequiométrica da base apropriada (tal como hidróxido, carbonato, bicarbonato ou os semelhantes de Na, Ca, Mg, ou K), ou reagindo-se as formas de base livre destes compostos com uma quantidade estequiométrica do ácido apropriado. Tais reações são tipicamente realizadas em água ou em um solvente orgânico, ou em uma mistura dos dois. No geral, o uso de meios não aquosos como éter, acetato de etila, etanol, isopropanol, ou acetonitrila é desejável, onde praticável. As listas de sais adequados adicionais podem ser encontradas, por exemplo, em “Remingtons Pharmaceutical Sciences”, 20a ed., Mack Publishing Company, Easton, Pa., (1985); e em “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” por Stahl e Wermuth (Wiley-VCH, Weinheim, Alemanha, 2002).[00122] The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg, or K), or by reacting. take the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, for example, in "Remingtons Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[00123] Além disso, os compostos aqui divulgados, incluindo seus sais, também podem ser obtidos na forma de seus hidratos, ou incluem outros solventes usados para a sua cristalização. Os compostos aqui divulgados podem inerente ou intencionalmente formar solvatos com solventes farmaceuticamente aceitáveis (incluindo água); portanto, é pretendido que a invenção abranja tanto a forma solvatada quanto a não solvatada.[00123] Furthermore, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds disclosed herein may inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); therefore, the invention is intended to cover both solvated and unsolvated form.
[00124] Em um outro aspecto, são aqui fornecidos métodos de preparar, métodos de separar, e métodos de purificar compostos da Fórmula (I). Os compostos aqui divulgados podem ter no geral vários centros assimétricos e são tipicamente representados na forma de misturas racêmicas. Esta invenção é intencionada a abranger misturas racêmicas, misturas parcialmente racêmicas e enantiômeros e diastereômeros separados.[00124] In another aspect, methods of preparing, methods of separating, and methods of purifying compounds of Formula (I) are provided herein. The compounds disclosed herein may generally have several asymmetric centers and are typically represented as racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diastereomers.
[00125] Os compostos aqui divulgados podem estar na forma de um dos isômeros possíveis, rotâmeros, atropisômeros, tautômeros ou misturas dos mesmos. Esta invenção é intencionada a abranger misturas de isômeros, rotâmeros, atropisômeros, tautômeros, isômeros, rotâmeros, atropisômeros, ou tautômeros parcialmente mistos, e isômeros, rotâmeros, atropisômeros, tautômeros separados.[00125] The compounds disclosed herein may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof. This invention is intended to encompass mixtures of isomers, rotamers, atropisomers, tautomers, isomers, rotamers, atropisomers, or partially mixed tautomers, and separate isomers, rotamers, atropisomers, tautomers.
[00126] Qualquer fórmula aqui dada também é intencionada a representar formas não rotuladas assim como formas isotopicamente rotuladas dos compostos. Os compostos isotopicamente rotulados têm as estruturas representadas pelas fórmulas dadas aqui exceto que um ou mais átomos são substituídos por um átomo tendo uma massa atômica ou número de massa selecionados. Os exemplos de isótopos que podem ser incorporados nos compostos aqui divulgados incluem isótopos de hidrogênio, carbono, nitrogênio, oxigênio, fósforo, flúor, e cloro, tais como 2H, 3H, 11C, 13C, 14C, 15 N 18F 31P 32P 36S 37 Cl e 125I respectivamente.[00126] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures represented by the formulas given here except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N 18F 31P 32P 36S 37 Cl and 125I respectively.
[00127] Em um outro aspecto, os compostos aqui divulgados incluem compostos isotopicamente rotulados como aqui definidos, por exemplo aqueles nos quais isótopos radioativos, tais como 3H, 14C e 18F, ou aqueles nos quais isótopos não radioativos, tais como 2H e 13C estão presentes. Tais compostos isotopicamente rotulados são úteis em estudos metabólicos (com 14C), estudos da cinética de reação (com, por exemplo 2H ou 3H), técnicas de detecção ou formação de imagem, tais como tomografia de emissão de pósitron (PET) ou tomografia computadorizada de emissão de fóton único (SPECT) incluindo ensaios de distribuição de tecido de medicamento ou substrato, ou no tratamento radioativo de pacientes. Em particular, um 18F ou composto rotulado pode ser particularmente desejável para estudos de PET ou SPECT. Os compostos isotopicamente rotulados da Fórmula (I) no geral podem ser preparados pelas técnicas convencionais conhecidas por aqueles habilitados na técnica ou pelos processos análogos a aqueles descritos nos Exemplos e Preparações anexas usando um reagente isotopicamente rotulado apropriado no lugar do reagente não rotulado previamente utilizado.[00127] In another aspect, the compounds disclosed herein include isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as 3H, 14C and 18F, or those in which non-radioactive isotopes such as 2H and 13C are gifts. Such isotopically labeled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with eg 2H or 3H), detection or imaging techniques such as positron emission tomography (PET) or computed tomography photon emission assays (SPECT) including drug or substrate tissue distribution assays, or in the radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of Formula (I) in general may be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labeled reagent in place of the previously used unlabelled reagent.
[00128] Além disso, a substituição com isótopos mais pesados, particularmente deutério (isto é, 2H ou D) pode proporcionar certas vantagens terapêuticas que resultam da maior estabilidade metabólica, por exemplo meia-vida in vivo aumentada ou exigências de dosagem diminuídas ou uma melhora no índice terapêutico. É entendido que deutério neste contexto é considerado como um substituinte de um composto da fórmula (I). A concentração de um tal isótopo mais pesado, especificamente deutério, pode ser definida pelo fator de enriquecimento isotópico. O termo “fator de enriquecimento isotópico” como aqui usado significa a razão entre a abundância isotópica e a abundância natural de um isótopo especificado. Se um substituinte em um composto desta invenção é indicado deutério, tal composto tem um fator de enriquecimento isotópico para cada átomo de deutério designado de pelo menos 3500 (52,5 % de incorporação de deutério em cada átomo de deutério designado), pelo menos 4000 (60 % de incorporação de deutério), pelo menos 4500 (67,5 % de incorporação de deutério), pelo menos 5000 (75 % de incorporação de deutério), pelo menos 5500 (82,5 % de incorporação de deutério), pelo menos 6000 (90 % de incorporação de deutério), pelo menos 6333,3 (95 % de incorporação de deutério), pelo menos 6466,7 (97 % de incorporação de deutério), pelo menos 6600 (99 % de incorporação de deutério), ou pelo menos 6633,3 (99,5 % de incorporação de deutério). Os solvatos farmaceuticamente aceitáveis de acordo com a invenção incluem aqueles em que o solvente de cristalização pode ser isotopicamente substituído, por exemplo D2O, acetona-d6, e DMSO- d6.[00128] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may provide certain therapeutic advantages that result from increased metabolic stability, for example increased in vivo half-life or decreased dosage requirements or a improvement in the therapeutic index. It is understood that deuterium in this context is considered to be a substituent of a compound of formula (I). The concentration of such a heavier isotope, specifically deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio of isotopic abundance to the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% incorporation of deuterium in each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) , or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates in accordance with the invention include those in which the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, and DMSO-d6.
[00129] De acordo com um aspecto, a invenção descreve composições farmacêuticas que incluem um composto da Fórmula (I), um composto listado na Tabela 1, e um carregador, adjuvante, ou veículo farmaceuticamente aceitáveis. A quantidade de composto nas composições aqui divulgadas é tal que é eficaz para inibir detectavelmente uma proteína cinase em uma amostra biológica ou em um paciente.[00129] According to one aspect, the invention describes pharmaceutical compositions which include a compound of Formula (I), a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the compositions disclosed herein is such that it is effective to detectably inhibit a protein kinase in a biological sample or in a patient.
[00130] Também será avaliado que certos dos compostos aqui divulgados podem existir na forma livre para o tratamento, ou onde apropriado, como um derivado farmaceuticamente aceitável dos mesmos. De acordo com a presente invenção, um derivado farmaceuticamente aceitável inclui, mas não é limitado a, pró-medicamentos, sais, ésteres, sais de tais ésteres, ou qualquer outro aduto ou derivado farmaceuticamente aceitáveis que na administração a um paciente em necessidade é capaz de fornecer, direta ou indiretamente, um composto como de outro modo aqui descrito, ou um metabólito ou resíduo dos mesmos.[00130] It will also be appreciated that certain of the compounds disclosed herein may exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. In accordance with the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, prodrugs, salts, esters, salts of such esters, or any other pharmaceutically acceptable adduct or derivative which upon administration to a patient in need is capable of to provide, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
[00131] Como descrito acima, as composições farmaceuticamente aceitáveis da invenção aqui divulgada adicionalmente compreendem um carregador, adjuvante, ou veículo farmaceuticamente aceitáveis, que, como aqui usados, incluem todos e quaisquer solventes, diluentes, ou outro veículo, dispersão ou auxiliares de suspensão líquidos, agentes ativos na superfície, agentes isotônicos, espessantes ou agentes emulsificantes, preservantes, aglutinantes sólidos, lubrificantes e os semelhantes, como adequado para a forma de dosagem particular desejada. Em Remington: The Science and Practice of Pharmacy, 21a edição, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Filadélfia, e Enciclopedia of Pharmaceutical Technology, eds. J. Swarbrick e J. C. Boilan, 1988-1999, Marcel Dekker, Nova Iorque, os conteúdos de cada uma das quais é aqui incorporada por referência, são divulgados vários carregadores usados na formulação de composições farmaceuticamente aceitáveis e técnicas conhecidas para a preparação dos mesmos. Exceto na medida em que qualquer meio carregador convencional seja incompatível com os compostos aqui divulgados, tais como pela produção de qualquer efeito biológico indesejável ou de outro modo interagindo em uma maneira deletéria com qualquer outro do(s) componente(s) da composição farmaceuticamente aceitável, o seu uso é considerado estar dentro do escopo desta invenção.[00131] As described above, the pharmaceutically acceptable compositions of the invention disclosed herein further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids. liquids, surface active agents, isotonic agents, thickeners or emulsifying agents, preservatives, solid binders, lubricants and the like, as suitable for the particular dosage form desired. In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boilan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, various carriers used in formulating pharmaceutically acceptable compositions and known techniques for preparing the same are disclosed. Except to the extent that any conventional carrier medium is incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition , its use is considered to be within the scope of this invention.
[00132] Alguns exemplos de materiais que podem servir como carregadores farmaceuticamente aceitáveis incluem, mas não são limitados a, trocadores de íon, alumina, estearato de alumínio, lecitina, proteínas séricas, tais como albumina sérica humana, substâncias tampão tais como fosfatos, glicina, ácido sórbico ou sorbato de potássio, misturas de glicerídeo parciais de ácidos graxos vegetais saturados, água, sais ou eletrólitos, tais como sulfato de protamina, hidrogeno fosfato de dissódio, hidrogeno fosfato de potássio, cloreto de sódio, sais de zinco, sílica coloidal, trissilicato de magnésio, polivinil pirrolidona, poliacrilatos, ceras, polímeros de bloco de polietileno-polioxipropileno, lanolina, açúcares tais como lactose, glicose e sacarose; amidos tais como amido de milho e amido de batata; celulose e seus derivados tais como carboximetil celulose sódica, etil celulose e acetato de celulose; tragacanto em pó; malte; gelatina; talco; excipientes tais como manteiga de cacau e ceras de supositório; óleos tais como óleo de amendoim, óleo de semente de algodão, óleo de açafrão, óleo de sésamo, óleo de oliva, óleo de milho e óleo de soja; glicóis; tais como propileno glicol ou polietileno glicol; ésteres tais como oleato de etila e laurato de etila; ágar; agentes tamponantes tais como hidróxido de magnésio e hidróxido de alumínio; ácido algínico; água isenta de pirógeno; solução salina isotônica; solução de Aneler; álcool etílico, e soluções tampão de fosfato, assim como outros lubrificantes não tóxicos compatíveis tais como lauril sulfato de sódio e estearato de magnésio, assim como agentes corantes, agentes de liberação, agentes de revestimento, agentes adoçantes, flavorizantes e perfumantes, preservantes e antioxidantes também podem estar presentes na composição, de acordo com o julgamento do formulador.[00132] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine , sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica , magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; baby powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, saffron oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Anler's solution; ethyl alcohol, and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants they may also be present in the composition, at the discretion of the formulator.
[00133] As composições aqui divulgadas podem ser administradas oral, parenteral, pela pulverização inalacional, tópica, retal, nasal, bucal, vaginalmente ou via um reservatório implantado. O termo “parenteral” como aqui usado inclui técnicas de injeção ou infusão subcutânea, intravenosa, intramuscular, intraarticular, intra-sinovial, intraesternal, intratecal, intraocular, intraepática, intralesional e intracraniana. Preferivelmente, as composições são administradas oral, intraperitoneal ou intravenosamente. As formas injetáveis estéreis das composições desta invenção podem ser suspensão aquosa ou oleaginosa. Estas suspensões podem ser formuladas de acordo com técnicas conhecidas na técnica usando agentes de dispersão ou umectação adequados e agentes de suspensão. A preparação injetável estéril também pode ser uma solução ou suspensão injetável estéril em um diluente ou solvente não tóxicos parenteralmente aceitáveis, por exemplo como uma solução em 1,3-butanodiol. Entre os veículos e solventes aceitáveis que podem ser utilizados são água, solução de Aneler e solução de cloreto de sódio isotônica. Além disso, óleos fixos estéreis são convencionalmente utilizadas como um solvente ou meio de suspensão.The compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasal, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Anler's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium.
[00134] Para este propósito, qualquer óleo fixo brando pode ser utilizado incluindo mono- ou diglicerídeos sintéticos. Ácidos graxos, tais como ácido oléico e seus derivados de glicerídeo são úteis na preparação de injetáveis, como o são os óleos naturais farmaceuticamente aceitáveis, tais como óleo de oliva ou óleo de mamona, especialmente nas suas versões polioxietiladas. Estas soluções ou suspensões oleosas também podem conter um diluente ou dispersante alcoólico de cadeia longa, tais como carboximetil celulose ou agentes de dispersão similares que são habitualmente usados na formulação de formas de dosagem farmaceuticamente aceitáveis incluindo emulsões e suspensões. Outros tensoativos habitualmente usados, tais como Tweens, Spans e outros agentes emulsificantes ou realçadores de biodisponibilidade que são habitualmente usados na fabricação de formas de dosagem sólidas, líquidas, ou outras farmaceuticamente aceitáveis também podem ser usados para os propósitos de formulação.[00134] For this purpose, any bland fixed oil can be used including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcoholic diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in formulating pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.
[00135] As composições farmaceuticamente aceitáveis desta invenção podem ser oralmente administradas em qualquer forma de dosagem oralmente aceitável incluindo, mas não limitado a, cápsulas, tabletes, suspensões ou soluções aquosas. No caso de tabletes para o uso oral, os carregadores habitualmente usados incluem lactose e amido de milho. Agentes lubrificantes, tais como estearato de magnésio, também são tipicamente adicionados. Para a administração oral em uma forma de cápsula, os diluentes úteis incluem lactose e amido de milho seco. Quando suspensões aquosas são requeridas para o uso oral, o ingrediente ativo é combinado com emulsificantes e agentes de suspensão. Se desejado, certos agentes adoçantes, flavorizantes ou corantes também podem ser adicionados.The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.
[00136] Alternativamente, as composições farmaceuticamente aceitáveis desta invenção podem ser administradas na forma de supositórios para a administração retal. Estes podem ser preparados misturando-se o agente com um excipiente não irritante adequado que é sólido na temperatura ambiente mas líquido na temperatura retal e portanto fundirá no reto para liberar o medicamento. Tais materiais incluem manteiga de cacau, cera de abelhas e polietileno glicóis.Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[00137] As composições farmaceuticamente aceitáveis desta invenção também podem ser administradas topicamente, em especial quando o alvo de tratamento inclui áreas ou órgãos facilmente acessíveis pela aplicação tópica, incluindo doenças dos olhos, da pele, ou do trato intestinal inferior. As formulações tópicas adequadas são facilmente preparadas para cada uma destas áreas ou órgãos.The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs.
[00138] A aplicação tópica para o trato intestinal inferior pode ser efetuada em uma formulação de supositório retal (ver acima) ou em uma formulação de enema adequada. Os emplastros topicamente transdérmico também podem ser usados. Para as aplicações tópicas, as composições farmaceuticamente aceitáveis podem ser formuladas em um unguento adequado contendo o componente ativo colocado em suspensão ou dissolvido em um ou mais carregadores. Os carregadores para a administração tópica dos compostos desta invenção incluem, mas não são limitados a, óleo mineral, vaselina líquida, vaselina branca, propileno glicol, polioxietileno, composto de polioxipropileno, cera emulsificante e água. Alternativamente, as composições farmaceuticamente aceitáveis podem ser formuladas em uma loção ou creme adequados contendo os componentes ativos colocados em suspensão ou dissolvidos em um ou mais carregadores farmaceuticamente aceitáveis. Os carregadores adequados incluem, mas não são limitados a, óleo mineral, monoestearato de sorbitano, polissorbato 60, cera de ésteres cetílicos, álcool cetearílico, 2-octildodecanol, álcool benzílico e água.[00138] Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches can also be used. For topical applications, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for the topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[00139] Para o uso oftálmico, as composições farmaceuticamente aceitáveis podem ser formuladas, por exemplo, como suspensões micronizadas em solução isotônica, solução salina estéril ajustada no pH ou outra solução aquosa, ou, preferivelmente, como soluções em solução salina isotônica, estéril ajustada no pH ou outra solução aquosa, com ou sem um preservante tal como cloreto de benzilalcônio. Alternativamente, para os usos oftálmicos, as composições farmaceuticamente aceitáveis podem ser formuladas em um unguento tal como vaselina. As composições farmaceuticamente aceitáveis desta invenção também podem ser administradas pelo aerossol nasal ou inalação. Tais composições são preparadas de acordo com técnicas bem conhecidas na técnica da formulação farmacêutica e podem ser preparadas como soluções em solução salina, utilizando álcool benzílico ou outro preservante adequado, promotores de absorção para realçar a biodisponibilidade, fluorocarbonetos, e/ou outros agentes de solubilização ou dispersão convencionais.[00139] For ophthalmic use, pharmaceutically acceptable compositions can be formulated, for example, as micronized suspensions in isotonic solution, pH-adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, sterile-adjusted saline solution at pH or other aqueous solution, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, pharmaceutically acceptable compositions may be formulated in an ointment such as petroleum jelly. The pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared in accordance with techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservative, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other solubilizing agents or conventional dispersion.
[00140] As formas de dosagem líquidas para a administração oral incluem, mas não são limitados a, emulsões, microemulsões, soluções, suspensões, xaropes e elixires farmaceuticamente aceitáveis. Além dos compostos ativos, as formas de dosagem líquidas podem conter diluentes inertes habitualmente usados na técnica tais como, por exemplo, água ou outros solventes, agentes de solubilização e emulsificadores tais como álcool etílico, álcool isopropílico, carbonato de etila, acetato de etila, álcool benzílico, benzoato de benzila, propileno glicol, 1,3-butileno glicol, dimetilformamida, óleos (em particular, óleos de semente de algodão, amendoim, milho, germe de trigo, oliva, mamona, e gergelim), glicerol, álcool tetraidrofurfurílico, polietileno glicóis e ésteres de ácido graxo de sorbitano, e misturas dos mesmos. Além dos diluentes inertes, as composições orais também podem incluir adjuvantes tais como agentes umectantes, emulsificantes e agentes de suspensão, adoçantes, flavorizantes, e agentes perfumantes.Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol , polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00141] As preparações injetáveis, por exemplo, as suspensões aquosas ou oleaginosas injetáveis estéreis podem ser formuladas de acordo com a técnica conhecida usando agentes de dispersão ou umectação e agentes de suspensão adequados. A preparação injetável estéril também pode ser uma solução, suspensão ou emulsão injetáveis estéreis em um diluente ou solvente não tóxicos parenteralmente aceitáveis, por exemplo, como uma solução em 1,3-butanodiol. Entre os veículos e solventes aceitáveis que podem ser utilizados são água, solução de Aneler, U.S.P. e solução isotônica de cloreto de sódio. Além disso, os óleos estéreis, fixos são convencionalmente utilizados como um solvente ou meio de suspensão. Para este propósito qualquer óleo fixo brando pode ser utilizado incluindo mono- ou diglicerídeos sintéticos. Além disso, ácidos graxos tais como ácido oléico são usados na preparação de injetáveis.Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Anler's solution, U.S.P. and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be used including synthetic mono- or diglycerides. Also, fatty acids such as oleic acid are used in the preparation of injectables.
[00142] As formulações injetáveis podem ser esterilizadas, por exemplo, pela filtração através de um filtro de retenção bacteriana, ou pela incorporação de agentes esterilizantes na forma de composições sólidas estéreis que podem ser dissolvidas ou dispersadas em água estéril ou outro meio injetável estéril antes do uso. De modo a prolongar o efeito de um composto aqui divulgado, é frequentemente desejável retardar a absorção do composto das injeções subcutânea ou intramuscular. Isto pode ser realizado pelo uso de uma suspensão líquida de material cristalino ou amorfo com solubilidade insuficiente em água. A taxa de absorção do composto depois depende da sua taxa de dissolução que, por sua vez, pode depender do tamanho do cristal e forma cristalina. Alternativamente, dissolver ou colocar em suspensão o composto em um veículo oleoso realiza a absorção retardada de uma forma de composto parenteralmente administrada.[00142] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before of use. In order to prolong the effect of a compound disclosed herein, it is often desirable to delay absorption of the compound from subcutaneous or intramuscular injections. This can be accomplished by using a liquid suspension of crystalline or amorphous material with insufficient water solubility. The compound's absorption rate then depends on its dissolution rate which, in turn, may depend on the crystal size and crystalline form. Alternatively, dissolving or suspending the compound in an oil vehicle effects delayed absorption of a parenterally administered form of the compound.
[00143] As formas de depósito injetáveis são fabricadas formando-se matrizes microencapsuladas do composto em polímeros biodegradáveis tais como polilactídeo-poliglicolídeo. Dependendo da razão de composto para polímero e da natureza do polímero particular utilizado, da taxa de liberação de composto pode ser controlada. Alguns exemplos não limitantes de outros polímeros biodegradáveis incluem poli(ortoésteres) e poli(anidridos). As formulações de depósito injetáveis também são preparadas aprisionando-se o composto em lipossomas ou microemulsões que são compatíveis com os tecidos corporais.[00143] The injectable depot forms are manufactured by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound to polymer ratio and the nature of the particular polymer used, the rate of compound release can be controlled. Some non-limiting examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00144] As composições para a administração retal ou vaginal são preferivelmente supositórios que podem ser preparados misturando-se os compostos desta invenção com excipientes ou carregadores não irritantes adequados tais como manteiga de cacau, polietileno glicol ou uma cera de supositório que são sólidos na temperatura ambiente mas líquidos na temperatura corporal e portanto fundem no reto ou cavidade vaginal e liberam o composto ativo.Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at temperature environment but liquids at body temperature and therefore fuse in the rectum or vaginal cavity and release the active compound.
[00145] As formas de dosagem sólidas para a administração oral incluem cápsulas, tabletes, pílulas, pós, e grânulos. Em tais formas de dosagem sólidas, o composto ativo é misturado com pelo menos um excipiente ou carregador inerte, farmaceuticamente aceitáveis tais como citrato de sódio ou fosfato de dicálcio e/ou a) enchedores ou extensores tais como amidos, lactose, sacarose, glicose, manitol, e ácido silicílico, b) aglutinantes tais como, por exemplo, carboximetilcelulose, alginatos, gelatina, polivinilpirrolidinona, sacarose, e acácia, c) umectantes tais como glicerol, d) agentes desintegrantes tais como ágar-ágar, carbonato de cálcio, amido de batata ou tapioca, ácido algínico, certos silicatos, e carbonato de sódio, e) solução de agentes retardantes tais como parafina, f) aceleradores de absorção tais como compostos de amônio quaternário, g) agentes de umectação tais como, por exemplo, álcool cetílico e monoestearato de glicerol, h) absorventes tais como caulim e argila bentonita, e i) lubrificantes tais como talco, estearato de cálcio, estearato de magnésio, polietileno glicóis sólidos, lauril sulfato de sódio, e misturas dos mesmos. No caso de cápsulas, tabletes e pílulas, a forma de dosagem também pode compreender agentes tamponantes.[00145] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, starch of potato or tapioca, alginic acid, certain silicates, and sodium carbonate, e) solution of retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, alcohol cetyl and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, lauryl sodium sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents.
[00146] As composições sólidas de um tipo similar também podem ser utilizadas como enchedores em cápsulas de gelatina enchidas moles e duras usando excipientes tais como lactose ou açúcar do leite assim como polietileno glicóis de peso molecular alto e os semelhantes. As formas de dosagem sólida de tabletes, drágeas, cápsulas, pílulas, e grânulos podem ser preparadas com revestimentos e cascas tais como revestimentos entéricos e outros revestimentos bem conhecidos na técnica da formulação farmacêutica. Elas podem opcionalmente conter agentes de opacificação e também podem ser de uma composição que liberem apenas o(s) ingrediente(s) ativo(s), ou preferencialmente, em uma certa parte do trato intestinal, opcionalmente, em uma maneira retardada. Alguns exemplos não limitantes de composições de embutimento que podem ser usadas incluem substâncias poliméricas e ceras. As composições sólidas de um tipo similar também podem ser utilizadas como enchedores em cápsulas de gelatina enchidas moles e duras usando excipientes tais como lactose ou açúcar de leite assim como polietileno glicóis de peso molecular alto e os semelhantes.[00146] Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, pills, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Some non-limiting examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
[00147] Os compostos ativos também podem estar na forma micro- encapsulada com um ou mais excipientes como mencionado acima. As formas de dosagem sólidas de tabletes, drágeas, cápsulas, pílulas, e grânulos podem ser preparados com revestimentos e cascas tais como revestimentos entéricos, revestimentos de controle de liberação e outros revestimentos bem conhecidos na técnica da formulação farmacêutica. Em tais formas de dosagem sólidas o composto ativo pode ser misturado com pelo menos um diluente inerte tal como sacarose, lactose ou amido. Tais formas de dosagem também podem compreender, como é prática normal, substâncias adicionais outras que não diluentes inertes, por exemplo, lubrificantes de tabletagem e outros auxiliares de tabletagem tais como estearato de magnésio e celulose microcristalina. No caso de cápsulas, tabletes e pílulas, as formas de dosagem também podem compreender agentes tamponantes. Elas podem opcionalmente conter agentes suavizantes e também podem ser de uma composição que elas liberem apenas o(s) ingrediente(s) ativo(s), ou preferencialmente, em uma certa parte do trato intestinal, opcionalmente, em uma maneira retardada. Alguns exemplos não limitantes de composições de embutimento que podem ser usadas incluem substâncias poliméricas e ceras.The active compounds can also be in micro-encapsulated form with one or more excipients as mentioned above. Solid dosage forms of tablets, pills, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents. They may optionally contain soothing agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Some non-limiting examples of embedding compositions which can be used include polymeric substances and waxes.
[00148] As formas de dosagem para a administração tópica ou transdérmica de um composto desta invenção incluem unguentos, pastas, cremes, loções, géis, pós, soluções, pulverizações, inalantes ou emplastros. O composto ativo é misturado sob condições estéreis com um carregador farmaceuticamente aceitável e qualquer um dos preservantes ou tampões necessários como podem ser requeridos. Formulação oftálmica, gotas para os ouvidos, e gotas oculares também são consideradas como estando dentro do escopo desta invenção. Adicionalmente, a presente invenção considera o uso de emplastros transdérmicos, que têm a vantagem adicionada de fornecer a liberação controlada de um composto ao corpo. Tais formas de dosagem podem ser feitas dissolvendo-se ou dispensando-se o composto no meio apropriado. Realçadores de absorção também podem ser usados para aumentar o fluxo do composto através da pele. A taxa pode ser controlada fornecendo-se uma membrana de controle da taxa ou pela dispersão do composto em uma matriz polimérica ou gel.Dosage forms for the topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any of the necessary preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also considered to be within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled release of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00149] Os compostos aqui divulgados são preferivelmente formulados na forma de unidade de dosagem para facilidade de administração e uniformidade de dosagem. A expressão “forma unitária de dosagem” como aqui usada refere-se a uma unidade fisicamente separada de agente apropriada para o paciente a ser tratado. Será entendido, entretanto, que o uso diário total dos compostos e composições aqui divulgados será decidido pelo médico atendente dentro do escopo do julgamento médico criterioso. O nível de dose eficaz específico para qualquer paciente ou organismo particulares dependerão de uma variedade de fatores incluindo o distúrbio que é tratado e a severidade do distúrbio; a atividade do composto específico utilizado; a composição específica utilizada; a idade, peso corporal, saúde geral, sexo e dieta do paciente; o tempo de administração, via de administração, e taxa de excreção do composto específico utilizado; a duração do tratamento; medicamentos usados em combinação ou coincidentes com o composto específico utilizado, e fatores semelhantes bem conhecidos nas técnicas médicas.The compounds disclosed herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically separate unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily use of the compounds and compositions disclosed herein will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; drugs used in combination or coincidental with the specific compound used, and similar factors well known in the medical arts.
[00150] A quantidade dos compostos da presente invenção que pode ser combinada com os materiais carregadores para produzir uma composição em uma forma de dosagem única variará dependendo do hospedeiro tratado, do modo particular de administração. Preferivelmente, as composições devem ser formuladas de modo que uma dosagem entre 0,01 e 200 mg/kg de peso corporal/dia do inibidor pode ser administrada a um paciente que recebe estas composições.The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01 and 200 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
[00151] Os compostos desta invenção podem ser administrados como o único agente farmacêutico ou em combinação com um ou mais outros agentes terapêuticos (farmacêuticos) adicionais onde a combinação não causa nenhum efeito adverso inaceitável. Isto pode ser de relevância particular para o tratamento de doenças hiper-proliferativos tais como câncer. Neste caso, o composto desta invenção pode ser combinado com agentes citotóxicos conhecidos, inibidores da transdução de sinal, ou com outros agentes anticâncer, assim como com misturas e combinações dos mesmos. Como aqui usados, agentes terapêuticos adicionais que são normalmente administrados para tratar uma doença, ou condição, particulares são conhecidos como “apropriados para a doença, ou condição, que são tratadas”. Como aqui usado, “agentes terapêuticos adicionais” é intencionado a incluir agentes quimioterapêuticos e outros agentes antiproliferativos.The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other therapeutic (pharmaceutical) agents where the combination does not cause any unacceptable adverse effects. This may be of particular relevance to the treatment of hyper-proliferative diseases such as cancer. In this case, the compound of this invention can be combined with known cytotoxic agents, signal transduction inhibitors, or with other anti-cancer agents, as well as mixtures and combinations thereof. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, that is being treated". As used herein, "additional therapeutic agents" is intended to include chemotherapeutic agents and other antiproliferative agents.
[00152] Por exemplo, agentes quimioterapêuticos ou outros agentes antiproliferativos podem ser combinados com os compostos desta invenção para tratar doença proliferativa ou câncer. Os exemplos de agentes quimioterapêuticos ou outros agentes antiproliferativos incluem inibidores de HDAC incluindo, mas não são limitados a, SAHA, MS-275, MGO 103, e aqueles descritos na WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO 2005/030705, WO 2005/092899, e agentes desmetilantes incluindo, mas não limitado a, 5-aza- dC, Vidaza e Decitabina e aqueles descritos na US 6.268137, US 5.578.716, US 5.919.772, US 6.054.439, US 6.184.211, US 6.020.318, US 6.066.625, US 6.506.735, US 6.221.849, US 6.953.783, US 11/393.380.[00152] For example, chemotherapeutic agents or other anti-proliferative agents can be combined with the compounds of this invention to treat proliferative disease or cancer. Examples of chemotherapeutic agents or other antiproliferative agents include HDAC inhibitors including, but not limited to, SAHA, MS-275, MGO 103, and those described in WO 2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US 2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO 2005/030705, WO 2005/092899, and demethylating agents including, but not limited to, not limited to, 5-aza-dC, Vidaza and Decitabine and those described in US 6,268137, US 5,578,716, US 5,919,772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US 6,221,849, US 6,953,783, US 11/393,380.
[00153] Em uma outra forma de realização da presente invenção, por exemplo, agentes quimioterapêuticos ou outros agentes antiproliferativos podem ser combinado com os compostos desta invenção para tratar doenças proliferativas e câncer. Os exemplos de agentes quimioterapêuticos conhecidos incluem, mas não são limitados a, por exemplo, outras terapias ou agentes anticâncer que podem ser usados em combinação com os agentes anticâncer inventivos da presente invenção e incluem cirurgia, radioterapia (em alguns exemplos, radiação gama, radioterapia de feixe de neutron, radioterapia de feixe de elétron, terapia de próton, braquiterapia, e isótopos radioativos sistêmicos, para mencionar uns poucos), terapia endócrina, taxanos (paclitaxel, taxotere), derivados de platina (cisplatina, carboplatina, oxaliplatina), modificadores de resposta biológica (interferons, interleucinas), fator de necrose de tumor (TNF, agentes que alvejam o receptor TRAIL, para mencionar uns poucos), hipertermia e crioterapia, agentes para atenuar quaisquer efeitos adversos (por exemplo, antieméticos), e outros medicamentos quimioterapêuticos aprovados, incluindo, mas não limitados a, medicamentos alquilantes (clormetina, clorambucila, ciclofosfamida, ifosfamida, melfalan, etc), anti-metabólitos (metotrexato, raltitrexed, pemetrexed, etc), antagonistas de purina e antagonistas de pirimidina (6- mercaptopurina, 5-fluorouracila, citarabina, gencitabina), venenos antifuso (vinblastina, vincristina, vinorrelbina), podofilotoxinas (etoposida, irinotecano, topotecano), antibióticos (doxorrubicina, bleomicina, mitomicina), nitrosouréias (carmustina, lomustina), inibidores do ciclo celular (inibidores da cinesina mitótica KSP, CENP-E e inibidores de CDK), enzimas (asparaginase), hormônios (tamoxifeno, leuprolida, flutamida, megestrol, dexametasona), agentes antiangiogênicos (avastin e outros), anticorpos monoclonais (Belimumab (BENLYSTA®), brentuximab (ADCETRIS®), cetuximab (ERBITUX®), gentuzumab (MILOTARG®), ipilimumab (YERVOY®), ofatumumab (ARZERRA®), panitumumab (VECTIBIX®), ranibizumab (LUCENTIS®), rituximab (RITUXAN®), tositumomab (BEXXAR®), trastuzumab (HERCEPTIN®), inibidores da cinase (imatinib (GLEEVEC®), sunitinib (SUTENT®), sorafenib (NEXAVAR®), cetuximab (ERBITUX®), trastuzumab (HERCEPTIN®), erlotinib (TARCEVA®), gefitinib (IRESSA®), dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®), crizotinib (XALKORI®), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), e outros), e agentes para inibir ou ativar caminhos do câncer tais como os caminhos mTOR, HIF (fator induzido pela hipoxia) (tais como everolimus e tensirolimus) e outros. Para um debate mais compreensivo de terapias contra o câncer atualizado ver, http://www.nci.nih.gov/, uma lista dos medicamentos de oncologia aprovados pelo FDA em http://www.fda.gov/cder/cancer/druglist-rame.htm, e The Merck Manual, Décima oitava Ed. 2006, Os conteúdos inteiros das quais são por meio deste incorporadas por referência.[00153] In another embodiment of the present invention, for example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, for example, other anti-cancer therapies or agents that can be used in combination with the inventive anti-cancer agents of the present invention and include surgery, radiation therapy (in some examples, gamma radiation, radiation therapy of neutron beam, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, taxanes (paclitaxel, taxotere), platinum derivatives (cisplatin, carboplatin, oxaliplatin), modifiers of biological response (interferons, interleukins), tumor necrosis factor (TNF, agents that target the TRAIL receptor, to name a few), hyperthermia and cryotherapy, agents to mitigate any adverse effects (eg, antiemetics), and other medications approved chemotherapeutics, including, but not limited to, alkylating drugs (chlormethine, chlorambucil, cyclophosphamide, i. phosphamide, melphalan, etc.), anti-metabolites (methotrexate, raltitrexed, pemetrexed, etc), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine), antifuse poisons (vinblastine, vincristine, vinorelbine) , podophyllotoxins (etoposid, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), cell cycle inhibitors (KSP mitotic kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase) , hormones (tamoxifen, leuprolide, flutamide, megestrol, dexamethasone), antiangiogenic agents (avastin and others), monoclonal antibodies (Belimumab (BENLYSTA®), brentuximab (ADCETRIS®), cetuximab (ERBITUX®), gentuzumab (MILOTARG®), ipilimumab (YERVOY®), ofatumumab (ARZERRA®), panitumumab (VECTIBIX®), ranibizumab (LUCENTIS®), rituximab (RITUXAN®), tositumomab (BEXXAR®), trastuzumab (HERCEPTIN®), kinase inhibitors (imatinib (GLEEVEC®) , sunitinib (SUTENT®), sorafe nib (NEXAVAR®), cetuximab (ERBITUX®), trastuzumab (HERCEPTIN®), erlotinib (TARCEVA®), gefitinib (IRESSA®), dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®), crizotinib ( XALKORI®), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), and others), and agents to inhibit or activate cancer pathways such as the mTOR, HIF (factor) pathways induced by hypoxia) (such as everolimus and tensirolimus) and others. For a more comprehensive discussion of updated cancer therapies see, http://www.nci.nih.gov/, a list of FDA-approved oncology drugs at http://www.fda.gov/cder/cancer/ druglist-rame.htm, and The Merck Manual, Eighteenth Ed. 2006, the entire contents of which are hereby incorporated by reference.
[00154] Em uma outra forma de realização, os compostos aqui divulgados podem ser combinados, com agentes anticâncer citotóxicos. Alguns exemplos não limitantes de tais agentes podem ser encontrados na 13a Edição do Merck Index (2001). Estes agentes incluem, por nenhuma via de limitação, asparaginase, bleomicina, carboplatina, carmustina, clorambucila, cisplatina, colaspase, ciclofosfamida, citarabina, dacarbazina, dactinomicina, daunorrubicina, doxorrubicina (adriamicina), epirrubicina, etoposida, 5- fluorouracila, hexametilmelamina, hidróxi-uréia, ifosfamida, irinotecano, leucovorin, lomustina, mecloretamina, 6-mercaptopurina, mesna, metotrexato, mitomicina C, mitoxantrona, prednisolona, prednisona, procarbazina, raloxifeno, estreptozocina, tamoxifeno, tioguanina, topotecano, vinblastina, vincristina, e vindesina.[00154] In another embodiment, the compounds disclosed herein may be combined with cytotoxic anti-cancer agents. Some non-limiting examples of such agents can be found in the 13th Edition of the Merck Index (2001). These agents include, by no means of limitation, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluoromethylamine -urea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocine, tamoxifene, thiovincricanine, guanine.
[00155] Outros medicamentos citotóxicos adequados para o uso com os compostos aqui divulgados incluem, mas não são limitados a, aqueles compostos conhecido ser usado no tratamento de doenças neoplásticas, tais como aquelas por exemplo em Goodman and GilmanÓs The Pharmacological Basis of Therapeutics (Nona Edição, 1996, McGraw-Hill). Estes agentes incluem, por nenhuma via de limitação, aminoglutetimida, L-asparaginase, azatioprina, 5-azacitidina cladribina, busulfano, dietilestilbestrol, 2,2Ó- difluorodesoxicitidina, docetaxel, eritrohidroxinoniladenina, etinil estradiol, 5-fluorodesoxiuridina, monofosfato de 5-fluorodesoxiuridina, fosfato de fludarabina, fluoximesterona, flutamida, caproato de hidróxi-progesterona, idarrubicina, interferon, acetato de medroxiprogesterona, acetato de megestrol, melfalan, mitotano, paclitaxel, pentostatina, N-fosfonoacetil-1- aspartato (PALA), plicamicina, semustina, teniposida, propionato de testosterona, tiotepa, trimetilmelamina, uridina, e vinorrelbina.[00155] Other cytotoxic drugs suitable for use with the compounds disclosed herein include, but are not limited to, those compounds known to be used in the treatment of neoplastic diseases, such as those for example in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill). These agents include, by no means of limitation, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2,2O-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-monofluorophosphate fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-1-aspartate (PALA), plicamycin, semustine , testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.
[00156] Outros agentes anticâncer citotóxicos adequados para o uso em combinação com os compostos aqui divulgados também incluem os princípios citotóxicos recém descobertos tais como oxaliplatina, gencitabina, capecitabina, epotilona e seus derivados naturais ou sintéticos, temozolomida (Quinn et al., J. Clin. Oncology, 2003, 21(4), 646-651), tositumomab (Bexxar®), trabedectina (Vidal et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstrato 3181), e os inibidores da proteína de fuso de cinesina Eg5 (Wood, et al. Curr. Opin. Pharmacol., 2001, 1, 370377).Other cytotoxic anticancer agents suitable for use in combination with the compounds disclosed herein also include newly discovered cytotoxic principles such as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic derivatives, temozolomide (Quinn et al., J. Clin. Oncology, 2003, 21(4), 646-651), tositumomab (Bexxar®), trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3181), and protein inhibitors of Eg5 kinesin fusion (Wood, et al. Curr. Opin. Pharmacol., 2001, 1, 370377).
[00157] Em uma outra forma de realização, os compostos aqui divulgados podem ser combinados com outros inibidores da transdução de sinal. Alguns exemplos não limitantes de tais agentes incluem terapias de anticorpo tal como trastuzumab (HERCEPTIN®), cetuximab (ERBITUX®), ipilimumab (YERVOY®) e pertuzumab. Os exemplos de tais terapias também incluem, por nenhuma via de limitação, inibidores da cinase de molécula pequena tais como imatinib (GLEEVEC®), sunitinib (SUTENT®), sorafenib (NEXAVAR®), erlotinib (TARCEVA®), gefitinib (IRESSA®), dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®), crizotinib (XALKORI®), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 (Folkes, et al., J. Med. Chem., 2008, 51: 5522), BZE235, e outros.[00157] In another embodiment, the compounds disclosed herein can be combined with other signal transduction inhibitors. Some non-limiting examples of such agents include antibody therapies such as trastuzumab (HERCEPTIN®), cetuximab (ERBITUX®), ipilimumab (YERVOY®) and pertuzumab. Examples of such therapies also include, by no means of limitation, small molecule kinase inhibitors such as imatinib (GLEEVEC®), sunitinib (SUTENT®), sorafenib (NEXAVAR®), erlotinib (TARCEVA®), gefitinib (IRESSA® ), dasatinib (SPRYCEL®), nilotinib (TASIGNA®), lapatinib (TYKERB®), crizotinib (XALKORI®), ruxolitinib (JAKAFI®), vemurafenib (ZELBORAF®), vandetanib (CAPRELSA®), pazopanib (VOTRIENT®), afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, crenolanib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib, cediranib, innitinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, vertibanib, MS, vitalipib, 76, trametinib, 76 JNJ38877605, TKI2 58, GDC-0941 (Folkes, et al., J. Med. Chem., 2008, 51: 5522), BZE235, et al.
[00158] Em uma outra forma de realização, os compostos aqui divulgados podem ser combinados com inibidores da histona desacetilase. Alguns exemplos não limitantes de tais agentes incluem ácido suberoilanilida hidroxâmico (SAHA), LAQ-824 (Ottmann, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstrato 3024), LBH-589 (Beck, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstrato 3025), MS-275 (Ryan, et al. Proceedings of the American Association of Cancer Research 2004, 45, abstrato 2452), FR-901228 (Piekarz, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstrato 3028) e MGCDOl 03 (US 6.897.220).[00158] In another embodiment, the compounds disclosed herein can be combined with histone deacetylase inhibitors. Some non-limiting examples of such agents include suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3024), LBH-589 (Beck, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3025), MS-275 (Ryan, et al. Proceedings of the American Association of Cancer Research 2004, 45, abstract 2452), FR-901228 (Piekarz, et al. Proceedings of the American Society for Clinical Oncology 2004, 23, abstract 3028) and MGCDOl 03 (US 6,897,220).
[00159] Em uma outra forma de realização, os compostos aqui divulgados podem ser combinados com outros agentes anticâncer tais como inibidores de proteassoma, e inibidores de mTOR. Estes incluem, por nenhuma via de limitação, bortezomib, e CCI-779 (Wu, et al., Proceedings of the American Association of Cancer Research 2004, 45, abstrato 3849). Os compostos aqui divulgados podem ser combinados com outros agentes anticâncer tais como inibidores da topoisomerase, incluindo mas não limitado a camptotecina.In another embodiment, the compounds disclosed herein can be combined with other anti-cancer agents such as proteasome inhibitors, and mTOR inhibitors. These include, by no means of limitation, bortezomib, and CCI-779 (Wu, et al., Proceedings of the American Association of Cancer Research 2004, 45, abstract 3849). The compounds disclosed herein can be combined with other anti-cancer agents such as topoisomerase inhibitors, including but not limited to camptothecin.
[00160] Estes agentes adicionais podem ser administrados separadamente da composição contendo composto, como parte de um regime de dosagem múltipla. Alternativamente, estes agentes podem ser parte de uma forma de dosagem única, misturados junto com o composto desta invenção em uma composição única. Se administradas como parte de um regime de dosagem múltipla, os dois agentes ativos podem ser submetidos simultânea, sequecialmente ou dentro de um período de tempo de um outro que resultaria na atividade desejada dos agentes.These additional agents may be administered separately from the compound-containing composition as part of a multiple dosage regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of this invention in a single composition. If administered as part of a multiple dosage regimen, the two active agents can be subjected simultaneously, sequentially, or within a time period of one another that would result in the desired activity of the agents.
[00161] A quantidade tanto do composto quanto do agente terapêutico adicional (naquelas composições que compreendem um agente terapêutico adicional como descrito acima) que podem ser combinados com os materiais carregadores para produzir uma forma de dosagem única variará dependendo do hospedeiro tratado e do modo particular de administração. Normalmente, a quantidade de agente terapêutico adicional presente nas composições desta invenção não serão maiores do que a quantidade que normalmente seria administrada em uma composição compreendendo este agente terapêutico como o único agente ativo. Preferivelmente, a quantidade de agente terapêutico adicional nas composições presentemente divulgadas variarão de cerca de 50 % a 100 % da quantidade normalmente presente em uma composição compreendendo este agente como o único agente terapeuticamente ativo. Nestas composições que compreendem um agente terapêutico adicional, este agente terapêutico adicional e o composto desta invenção podem atuar sinergisticamente.The amount of both the compound and the additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular manner administration. Typically, the amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising this therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising this agent as the only therapeutically active agent. In those compositions which comprise an additional therapeutic agent, this additional therapeutic agent and the compound of this invention may act synergistically.
[00162] A invenção descreve composições farmacêuticas que incluem um composto da Fórmula (I), ou um composto listado na Tabela 1, e um carregador, adjuvante, ou veículo farmaceuticamente aceitáveis. A quantidade do composto nas composições aqui divulgadas é tal que seja eficaz para inibir ou modular detectavelmente uma proteína cinase, tal como a atividade de PI3K ou mTOR. Os compostos aqui divulgados são úteis em terapia como agentes antineoplasia ou para minimizar efeitos deletérios da sinalização de PI3K ou mTOR.The invention describes pharmaceutical compositions which include a compound of Formula (I), or a compound listed in Table 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the compositions disclosed herein is such that it is effective to detectably inhibit or modulate a protein kinase, such as PI3K or mTOR activity. The compounds disclosed herein are useful in therapy as anti-cancer agents or to minimize deleterious effects of PI3K or mTOR signaling.
[00163] Os compostos aqui divulgados seriam úteis, mas não limitados, para a prevenção ou tratamento de doenças, condição, ou distúrbio proliferativos em um paciente pela administração ao paciente de um composto ou uma composição aqui divulgada em uma quantidade eficaz. Tais doenças, condições, ou distúrbios incluem câncer, particularmente câncer metastático, aterosclerose e fibrose pulmonar.The compounds disclosed herein would be useful, but not limited to, for preventing or treating a proliferative disease, condition, or disorder in a patient by administering to the patient a compound or composition disclosed herein in an effective amount. Such diseases, conditions, or disorders include cancer, particularly metastatic cancer, atherosclerosis, and pulmonary fibrosis.
[00164] Os compostos aqui divulgados seriam úteis para o tratamento de neoplasma incluindo câncer e metástase, incluindo, mas não limitado a: carcinoma tal como câncer da bexiga, mama, cólon, rim, fígado, pulmão (incluindo câncer pulmonar de célula pequena), esôfago, vesícula biliar, ovário, pâncreas, estômago, pescoço, tireóide, próstata, e pele (incluindo carcinoma de célula escamosa); tumores hematopoiéticos de linhagem linfóide (incluindo leucemia, leucemia linfocítica aguda, leucemia linfoblástica aguda, linfoma de célula B, linfoma de célula T, linfoma de Hodgkin, linfoma de não Hodgkin, linfoma de célula pilosa e linfoma de Burkett); tumores hematopoiéticos de linhagem mielóide (incluindo leucemias mielógenas agudas e crônicas, síndrome mielodisplástica e leucemia promielocítica); tumores de origem mesenquimatosa (incluindo fibrossarcoma e rabdomiossarcoma, e outros sarcomas, por exemplo de tecido mole e osso); tumores do sistema nervoso central e periférico (incluindo astrocitoma, neuroblastoma, glioma e schvanomas); e outros tumores (incluindo melanoma, seminoma, teratocarcinoma, osteossarcoma, xeroderoma pigmentoso, queratoctantoma, câncer folicular da tireóide e sarcoma de Kapose).The compounds disclosed herein would be useful for the treatment of neoplasm including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer) , esophagus, gallbladder, ovary, pancreas, stomach, neck, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, for example of soft tissue and bone); central and peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma, and schvanomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderoma pigmentosum, keratoctantoma, thyroid follicular cancer, and Kapose's sarcoma).
[00165] Os compostos também seriam úteis para o tratamento de condições oftalmológicas tais como rejeição ao enxerto córneo, neovascularização ocular, neovascularização retinal incluindo neovascularização a seguir de lesão ou infecção, retinopatia diabética, fibroplasia retrolental e glaucoma neovascular; isquemia retinal; hemorragia vítrea; doenças ulcerativas tais como úlcera gástrica; patológicas, mas não malignas, condições tais como hemangiomas, incluindo hemaginoma infantil, angiofibroma da nasofaringe e necrose avascular do osso; e distúrbios do sistema reprodutivo feminino tais como endometriose. Os compostos também são úteis para o tratamento de edema, e condições de hiperpermeabilidade vascular.The compounds would also be useful for the treatment of ophthalmologic conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; pathological, but not malignant, conditions such as hemangiomas, including infantile hemaginoma, nasopharyngeal angiofibroma, and avascular bone necrosis; and disorders of the female reproductive system such as endometriosis. The compounds are also useful for treating edema, and vascular hyperpermeability conditions.
[00166] Os compostos aqui divulgados também são úteis no tratamento de condições diabéticas tais como retinopatia diabética e microangiopatia. Os compostos aqui divulgados também são úteis na redução do fluxo sanguíneo em um tumor em um indivíduo. Os compostos aqui divulgados também são úteis na redução da metástase de um tumor em um indivíduo.The compounds disclosed herein are also useful in the treatment of diabetic conditions such as diabetic retinopathy and microangiopathy. The compounds disclosed herein are also useful in reducing blood flow to a tumor in an individual. The compounds disclosed herein are also useful in reducing tumor metastasis in an individual.
[00167] Além de serem úteis para o tratamento humano, estes compostos também são úteis para o tratamento veterinário de animais de estimação, animais exóticos e animais de fazenda, incluindo mamíferos, roedores, e os semelhantes. Os animais mais preferidos incluem cavalos, cães, e gatos. Como aqui usados, os compostos aqui divulgados incluem os derivados farmaceuticamente aceitáveis dos mesmos.[00167] In addition to being useful for human treatment, these compounds are also useful for veterinary treatment of pets, exotic animals and farm animals, including mammals, rodents, and the like. The most preferred animals include horses, dogs, and cats. As used herein, the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
[00168] Onde a forma plural é usada para os compostos, sais, e os semelhantes, isto também é considerado significar um único composto, sal e os semelhantes.[00168] Where the plural form is used for compounds, salts, and the like, this is also taken to mean a single compound, salt and the like.
[00169] O método de tratamento que inclui administrar um composto ou composição aqui divulgados pode incluir ainda administrar ao paciente um agente terapêutico adicional (terapia de combinação) selecionado de: um agente quimioterapêutico ou antiproliferativo, ou um agente antiinflamatório, em que o agente terapêutico adicional é apropriado para a doença que é tratada e o agente terapêutico adicional é administrado junto com um composto ou composição aqui divulgados como uma forma de dosagem única ou separadamente do composto ou composição como parte de uma forma de dosagem múltipla. O agente terapêutico adicional pode ser administrado ao mesmo tempo como um composto aqui divulgado ou em um tempo diferente. No último caso, a administração pode ser escalonada, por exemplo, em 6 horas, 12 horas, 1 dia, 2 dias, 3 dias, 1 semana, 2 semanas, 3 semanas, 1 mês, ou 2 meses.The method of treatment which includes administering a compound or composition disclosed herein may further include administering to the patient an additional therapeutic agent (combination therapy) selected from: a chemotherapeutic or anti-proliferative agent, or an anti-inflammatory agent, wherein the therapeutic agent additional is appropriate for the disease being treated and the additional therapeutic agent is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form. The additional therapeutic agent can be administered at the same time as a compound disclosed herein or at a different time. In the latter case, administration may be staggered, for example, over 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
[00170] A invenção também descreve um método de inibir o crescimento de uma célula que expressa PI3K ou mTOR, que inclui contatar a célula com um composto ou composição aqui divulgados, causando deste modo a inibição do crescimento da célula. Alguns exemplos não limitantes de uma célula cujo crescimento pode ser inibido incluem: uma célula de câncer mamário, uma célula de câncer colorretal, uma célula de câncer pulmonar, uma célula de carcinoma papilar, uma célula de câncer prostático, uma célula de linfoma, uma célula de câncer de cólon, uma célula de câncer pancreático, uma célula de câncer ovariano, uma célula de câncer cervical, uma célula de câncer do sistema nervoso central, uma célula de sarcoma osteogênico, uma célula de carcinoma renal, uma célula de carcinoma hepatocelular, uma célula de câncer de bexiga, uma célula de carcinoma gástrico, uma célula de carcinoma escamoso da cabeça e pescoço, uma célula de melanoma, ou uma célula de leucemia.The invention also describes a method of inhibiting the growth of a cell expressing PI3K or mTOR, which includes contacting the cell with a compound or composition disclosed herein, thereby causing inhibition of cell growth. Some non-limiting examples of a cell whose growth can be inhibited include: a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cell, osteogenic sarcoma cell, renal carcinoma cell, hepatocellular carcinoma cell , a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous cell carcinoma, a melanoma cell, or a leukemia cell.
[00171] A invenção fornece um método de inibir ou modular a atividade de PI3K ou mTOR em uma amostra biológica compreendendo contatar a amostra biológica com um composto ou composição aqui divulgados. O termo “amostra biológica” como aqui usado, significa uma amostra fora de um organismo vivo e inclui, sem limitação, culturas de célula ou extratos das mesmas; material de biópsia obtido de um mamífero ou extratos do mesmo; e sangue, saliva, urina, fezes, sêmen, lágrimas, ou outros fluídos corporais ou extratos dos mesmos. A inibição ou modulação da atividade da cinase, particularmente atividade de PI3K ou mTOR, em uma amostra biológica são úteis para uma variedade de propósitos conhecidos por uma pessoa de habilidade na técnica. Os exemplos de tais propósitos incluem, mas não são limitados a, transfusão de sangue, transplante de órgão, armazenagem de espécimes biológicos, e ensaios biológicos.The invention provides a method of inhibiting or modulating PI3K or mTOR activity in a biological sample comprising contacting the biological sample with a compound or composition disclosed herein. The term "biological sample" as used herein means a sample outside of a living organism and includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts from it; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. Inhibition or modulation of kinase activity, particularly PI3K or mTOR activity, in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.
[00172] Em certas formas de realização da presente invenção uma “quantidade eficaz” ou “dose eficaz” do composto ou composição farmaceuticamente aceitável é aquela quantidade eficaz para tratar ou diminuir a severidade de um ou mais dos distúrbios anteriormente mencionados. Os compostos e composições, de acordo com o método da presente invenção, podem ser administrados usando qualquer quantidade e qualquer via de administração eficaz para tratar ou diminuir a severidade do distúrbio ou doença. A quantidade exata requerida variará de indivíduo para indivíduo, dependendo da espécie, idade, e condição geral do indivíduo, da severidade da infecção, do agente particular, do seu modo de administração, e dos semelhantes. Um composto ou composição também podem ser administrados com um ou mais outros agentes terapêuticos, como debatido acima.In certain embodiments of the present invention an "effective amount" or "effective dose" of the pharmaceutically acceptable compound or composition is that amount effective to treat or lessen the severity of one or more of the aforementioned disorders. The compounds and compositions according to the method of the present invention can be administered using any amount and any route of administration effective to treat or lessen the severity of the disorder or disease. The exact amount required will vary from individual to individual depending on the species, age, and general condition of the individual, the severity of the infection, the particular agent, its mode of administration, and the like. A compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
[00173] Os compostos desta invenção ou composições farmacêuticas dos mesmos também podem ser usados para revestir um dispositivo médico implantável, tal como próteses, válvulas artificiais, enxertos vasculares, stents e catéteres. Os stents vasculares, por exemplo, têm sido usados para superar a restenose (re-estreitamento dos vasos depois da lesão). Entretanto, pacientes usando stents ou outros dispositivos implantáveis correm o risco de formação de coágulo ou ativação de plaqueta. Estes efeitos indesejáveis podem ser prevenidos ou mitigados pelo pré-revestimento do dispositivo com uma composição farmaceuticamente aceitável compreendendo um composto desta invenção.The compounds of this invention or pharmaceutical compositions thereof can also be used to coat an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of vessels after injury). However, patients using stents or other implantable devices are at risk for clot formation or platelet activation. These undesirable effects can be prevented or mitigated by precoating the device with a pharmaceutically acceptable composition comprising a compound of this invention.
[00174] Os revestimentos adequados e a preparação geral de dispositivos implantáveis revestidos são descritos nas Patentes U.S. Nos. 6.099.562; 5.886.026; e 5.304.121, os conteúdos de cada um dos quais são aqui incorporados por referência. Os revestimentos são tipicamente materiais poliméricos biocompatíveis tais como um polímero de hidrogel, polimetildissiloxano, policaprolactona, polietileno glicol, ácido poliláctico, vinil acetato de etileno, e misturas dos mesmos. Os revestimentos podem ser opcionalmente cobertos ainda por uma cobertura de topo adequada de fluorossilício e, polissacarídeos, polietileno glicol, fosfolipídeos ou combinações dos mesmos para comunicar características de liberação controlada na composição. Os dispositivos implantáveis revestidos com um composto desta invenção são uma outra forma de realização da presente invenção. Os compostos também podem ser revestidos sobre dispositivos médicos implantáveis, tais como pérolas, ou co-formuladas com um polímero ou outra molécula, para fornecer um “depósito de medicamento” permitindo assim que o medicamento seja liberado em um período de tempo mais longo do que a administração de uma solução aquosa do medicamento.Suitable coatings and general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121, the contents of each of which are incorporated herein by reference. Coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings can optionally be further covered by a suitable topcoat of fluorosilicon and, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention. Compounds can also be coated onto implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot" thus allowing the drug to be released in a longer period of time than administering an aqueous solution of the drug.
[00175] De modo a ilustrar a invenção, os seguintes exemplos são incluídos. Entretanto, deve ser entendido que estes exemplos não limitam a invenção e são apenas intencionados a sugerir um método de praticar a invenção.[00175] In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only intended to suggest a method of practicing the invention.
[00176] No geral, os compostos nesta invenção podem ser preparados pelos métodos aqui descritos, em que os substituintes são como definidos para a fórmula (I), acima, exceto onde além disso mencionado. Os seguintes esquemas e exemplos não limitantes são apresentados para exemplificar ainda mais a invenção. As pessoas habilitadas na técnica reconhecerão que as reações químicas aqui descritas podem ser facilmente adaptadas para preparar vários outros compostos aqui divulgados, e métodos alternativos para preparar os compostos desta invenção são julgados estar dentro do escopo desta invenção. Por exemplo, a síntese de compostos não exemplificados de acordo com a invenção pode ser realizada com êxito pelas modificações evidentes para aqueles habilitados na técnica, por exemplo, protegendo-se apropriadamente grupos interferentes, pela utilização de outros reagentes adequados conhecidos na técnica outra que não aquelas descritas, e/ou fazendo-se modificações de rotina das condições de reação. Alternativamente, outras reações aqui divulgadas ou conhecidas na técnica serão reconhecidas como tendo aplicabilidade para preparar outros compostos aqui divulgados.In general, the compounds in this invention can be prepared by the methods described herein, wherein the substituents are as defined for formula (I), above, except where otherwise mentioned. The following non-limiting schemes and examples are presented to further exemplify the invention. Persons skilled in the art will recognize that the chemical reactions described herein can be readily adapted to prepare various other compounds disclosed herein, and alternative methods for preparing the compounds of this invention are believed to be within the scope of this invention. For example, the synthesis of compounds not exemplified according to the invention can be successfully carried out by modifications evident to those skilled in the art, for example, by appropriately protecting interfering groups, by the use of other suitable reagents known in the art other than those described, and/or making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability to preparing other compounds disclosed herein.
[00177] Nos exemplos descritos abaixo, a menos que de outro modo indicado todas as temperaturas são apresentadas em graus Celsius. Os reagentes foram adquiridos de fornecedores comerciais tais como Aldrich Chemical Company, Arco Chemical Company e Alfa Chemical Company, Shanghai Medpep. Co Ltd, Aladdin-Shanghai Jinchun Reagents, Ltd, e foram usados sem outra purificação a menos que de outro modo indicado. Os solventes comuns foram adquiridos de fornecedores comerciais tais como Shantou Xilong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tainjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., e Qingdao Ocean Chemical Factory.[00177] In the examples described below, unless otherwise indicated all temperatures are given in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, Shanghai Medpep. Co Ltd, Aladdin-Shanghai Jinchun Reagents, Ltd, and have been used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou Xilong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tainjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.
[00178] THF anidro, dioxano, tolueno, e éter foram obtidos refluxando-se o solvente com sódio. CH2Cl2 e CHCl3 anidros foram obtidos refluxando-se o solvente com CaH2. EtOAc, PE, hexanos, DMA e DMF foram tratados com Na2SO4 anidro antes do uso.Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous CH2Cl2 and CHCl3 were obtained by refluxing the solvent with CaH2. EtOAc, PE, hexanes, DMA and DMF were treated with anhydrous Na2SO4 prior to use.
[00179] As reações apresentadas abaixo foram feitas no geral sob uma pressão positiva de nitrogênio ou argônio ou com um tubo de secagem (a menos que de outro modo estabelecido) em solventes anidros, e os frascos de reação foram tipicamente adaptados com septos de borracha para a introdução de substratos e reagentes por intermédio de seringa. A vidraria foi secada em estufa e/ou secada por calor. A cromatografia em coluna foi conduzida usando uma coluna de gel de sílica. O gel de sílica (300 a 400 malhas) foi adquirido da Qingdao Ocean Chemical Factory. Os espectros de RMN1H foram registrados com um espectrômetro Bruker de 400 MHz ou um espectrômetro Bruker de 600 MHz na temperatura ambiente. Os espectros de RMN1H[00179] The reactions shown below were generally carried out under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction vials were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. The glassware was oven dried and/or heat dried. Column chromatography was conducted using a silica gel column. Silica gel (300 to 400 mesh) was purchased from Qingdao Ocean Chemical Factory. 1H NMR spectra were recorded with a Bruker 400 MHz spectrometer or a Bruker 600 MHz spectrometer at room temperature. 1H NMR spectra
[00180] foram obtidos como soluções de CDCl3, DMSO-d6, CD3OD ou acetona-d6 (relatadas em ppm), usando TMS (0 ppm) ou clorofórmio (7,26 ppm) como o padrão de referência. Quando as multiplicidades de pico são relatadas, as seguintes abreviações são usadas: s (singleto), d (dubleto), t (tripleto), m (multipleto), br (ampliado), dd (dubleto de dubletos), dt (dubleto de tripletos). As constantes de ligação, quando dadas, são relatadas em Hertz (Hz).[00180] were obtained as solutions of CDCl3, DMSO-d6, CD3OD or acetone-d6 (reported in ppm), using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (enlarged), dd (doublet of doublets), dt (doublet of triplets). Binding constants, when given, are reported in Hertz (Hz).
[00181] Os dados espectrais de massa (MS) de baixa resolução foram no geral determinados em um Agilent 6120 Quadripolar HPLC-MS (Zorbax SB-C18, 2,1 x 30 mm, 3,5 mícrons, 6 minutos de condução, 0,6 ml/min de taxa de fluxo, 5 % a 95 % (0,1 % de ácido fórmico em CH3CN) em (0,1 % de ácido fórmico em H2O)) com detecção UV a 210 nm/254 nm e modo de ionização de eletropulverização (ESI).[00181] Low resolution mass spectral (MS) data were generally determined on an Agilent 6120 Quadripolar HPLC-MS (Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 minutes conduction, 0 0.6 ml/min flow rate, 5% to 95% (0.1 % formic acid in CH3CN) in (0.1 % formic acid in H2O)) with UV detection at 210 nm/254 nm and mode of electrospray ionization (ESI).
[00182] As purezas dos compostos foram avaliadas pela Agilent 1260 Pre-HPLC ou Bomba Calesep 250 Pré-HPLC (Coluna NOVASEP 50/80 mm DAC) com detecção UV a 210 nm/254 nm.The purities of the compounds were evaluated by the Agilent 1260 Pre-HPLC or Calesep 250 Pre-HPLC Pump (NOVASEP column 50/80 mm DAC) with UV detection at 210 nm/254 nm.
[00183] As seguintes abreviações são usadas por todo o relatório descritivo: ATP trifosfato de adenosina AcOH, HOAc, CH3COOH ácido acético AIBN azodiisobutironitrila BBr3 tribrometo de boro Bu4NF fluoreto de tetrabutilamônio BINAP 2,2Ó-bis(difenilfosfino)-l,1Ó-binaftila BOC, Boc butiloxicarbonila BSA albumina sérica bovina n-BuOH álcool butílico n-BuLi n-butillítio CDCl3 clorofórmio deuterado CCl4 tetracloreto de carbono CHCl3 clorofórmio CH2Cl2, DCM cloreto de metileno CH3SO2Cl, MsCl cloreto de 4-tolueno sulfonila Cs2CO3 Carbonato de césio CH3CN, MeCN acetonitrila CH3SO2Cl, MsCl cloreto de metanossulfonila Cs2CO3 carbonato de césio CuI iodeto cuproso DCC N,NÓ-Diciclohexilcarbodie DAST trifluoreto de dietilaminoenxofre DBU 1,8-Diazabiciclo[5,4,0]undec-7-eno DEAD azodicarboxilato de dimetila DIAD azodicarboxilato de diisopropila DIBAL hidreto de diisobutilalumínio DIEA, DIPEA, i-Pr2NEt diisopropiletilamina DMAP 4-dimetilaminopiridina DME dimetoxietano DMF dimetilformamida DMSO sulfóxido de dimetila DPPA difenilfosforil azida EDCI cloridreto de 1-(3-dimetilaminopropil)-3-etilcarbodiimida EtOAc, EA acetato de etila EtOH etanol Et2O éter dietílico Et3N, TEA trietilamina FBS soro bovino fetal g grama h hora HATU hexafluorofosfato de O-(7-azabenzotriazol-1-il)-N,N,NÓ,NÓ- tetrametilurônio HBr ácido bromídrico HBTU hexafluorofosfato de O-benzotriazol-1-il-N,N,NÓ,NÓ- tetrametilurônio H2O2 peróxido de hidrogênio HOAc,AcOH ácido acético HOBt hidrato de 1-hidróxi-benzotriazol i-Pr2NH diisopropilamina K2CO3 carbonato de potássio KOAc, CH3COOK Acetato de Potássio LiHMDS bis(trimetilsilil)amida de lítio LDA diisopropilamida de lítio MCPBA ácido meta-cloroperbenzóico MeI iodeto de metila MeOH, CH3OH metanol 2-MetF 2-metil tetraidrofurano MgSO4 sulfato de magnésio MsCl cloreto de metanossulfonila mL, ml mililitro N2 nitrogênio NaBH4 boroidreto de sódio NaBH3CN cianoboroidreto de sódio NaClO2 clorito de sódio NaH hidreto de sódio Na2CO3 carbonato de sódio NaHCO3 bicarbonato de sódio NaH2PO4 bifosfato de sódio NaO(t-Bu) terc-butóxido de sódio Na2SO4 sulfato de sódio NBS N-Bromossuccinimida NIS N-Iodossuccinimida NH3 amônia NH4Cl cloreto de amônio NMP N-metilpirrolidínio PBS solução salina tamponada com fosfato P(t-Bu)3 tri(terc-butil)fosfina Pd/C paládio em carbono Pd2(dba)3 bis(dibenzilidenoacetona) paládio Pd(dppf)Cl2 dicloreto de 1,1-bis(difenilfosfino)ferroceno paládio Pd(dppf)Cl2<H2Cl2 aduto de dicloro[1,rbis(difenilfosfmo)ferroceno] paládio(II) diclorometano Pd(PPh3)4 paládio tetracis trifenilfosfina Pd(PPh3)2Cl2 Cloreto de Bis(trifenilfosfina)paládio(II) PE éter de petróleo (60 a 90 oC) POCl3 oxicloreto de fósforo PCl5 cloreto de fósforo (V) PyBop hexafluorofosfato de benzotriazol-1-il-oxitripirrolidinofosfônio Pre-HPLC cromatografia líquida de alto desempenho preparativa RT, rt, r.t. temperatura ambiente Rt tempo de retenção TBAB brometo de tetrabutilamônio TBAF fluoreto de tetrabutil amônio TBAHSO4 hidrogeno sulfato de tetrabutilamônio TBTU tetrafluoroborato de O-benzotriazol-1-il-N,N,NÓ,NÓ- tetrametilurônio TFA ácido trifluoroacético TEAC carbonato de bis(tetra-etilamônio) THF tetraidrofurano μl microlitro X-Phos sal de p-Toluidina de 5-Bromo-4-cloro-3-indolilfosfato[00183] The following abbreviations are used throughout the specification: ATP adenosine triphosphate AcOH, HOAc, CH3COOH acetic acid AIBN azodiisobutyronitrile BBr3 boron tribromide Bu4NF tetrabutylammonium fluoride BINAP 2,2O-bis(diphenylphosphino)-1,1O-binaphthyl BOC, Boc butyloxycarbonyl BSA bovine serum albumin n-BuOH butyl alcohol n-BuLi n-butyllithium CDCl3 deuterated chloroform CCl4 carbon tetrachloride CHCl3 chloroform CH2Cl2, DCM methylene chloride CH3SO2Cl, MsCl 4-toluene sulfonyl chloride, Mesc CN Carbonate Cs2CO3 acetonitrile CH3SO2Cl, MsCl methanesulfonyl chloride Cs2CO3 cesium carbonate CuI cuprous iodide DCC N,NO-Dicyclohexylcarbodie DAST diethylaminosulfur trifluoride DBU 1,8-Diazabicyclo[5,4,0]undec-7-ene DEAD azodicarboxyadicarboxylate dimethyl azodicarboxylate DIBAL diisobutylaluminum hydride DIEA, DIPEA, i-Pr2NEt diisopropylethylamine DMAP 4-dimethylaminopyridine DME dimethoxyethane DMF dimethylformamide DMSO sulfoxide of dimethyl DPPA diphenylphosphoryl azide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc, EA ethyl acetate EtOH ethanol Et2O diethyl ether Et3N, TEA triethylamine FBS fetal bovine serum g gram h hour HATU O-(7-hexafluorophosphate) azabenzotriazol-1-yl)-N,N,NO,NO- tetramethyluronium HBr hydrobromic acid HBTU O-benzotriazol-1-yl-N,N,NO,NO-tetramethyluronium hexafluorophosphate H2O2 hydrogen peroxide HOAc,AcOH acetic acid HOBt hydrate of 1-hydroxy-benzotriazole i-Pr2NH diisopropylamine K2CO3 potassium carbonate KOAc, CH3COOK Potassium Acetate LiHMDS lithium bis(trimethylsilyl)amide LDA lithium diisopropylamide MCPBA meta-chloroperbenzoic acid MeI methyl iodide MeOH, CH3OH methanol 2-MetF methyl tetrahydrofuran MgSO4 magnesium sulfate MsCl methanesulfonyl chloride mL, ml milliliter N2 nitrogen NaBH4 sodium borohydride NaBH3CN sodium cyanoborohydride NaClO2 sodium chlorite NaH sodium hydride Na2CO3 sodium carbonate NaHCO3 sodium bicarbonate NaH2PO4 sodium biphosphate NaO(t-Bu) sodium tert-butoxide Na2SO4 sodium sulfate NBS N-Bromosuccinimide NIS N-Iodosuccinimide NH3 ammonia NH4Cl ammonium chloride NMP N-methylpyrrolidinium PBS phosphate-buffered saline P(t-Bu)3 tri(tert-butyl)phosphine Pd/C palladium on carbon Pd2(dba)3 bis(dibenzylideneacetone) palladium Pd(dppf)Cl2 1,1-bis(diphenylphosphino)ferrocene palladium palladium Pd(dppf)Cl2<H2Cl2 dichlorine adduct [1,rbis(diphenylphosphine)ferrocene] palladium(II) dichloromethane Pd(PPh3)4 palladium tetracis triphenylphosphine Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) chloride PE petroleum ether (60 to 90 oC) POCl3 oxychloride phosphorus PCl5 phosphorus (V) chloride PyBop benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate Pre-HPLC preparative high performance liquid chromatography RT, rt, rt room temperature Rt retention time TBAB tetrabutylammonium bromide TBAF tetrabutylammonium fluoride TBAHSO4 tetrabutylammonium hydrogen sulfate TBTU O-benzotriazol-1-yl-N,N,NO,NO-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid TEAC bis(tetra-carbonate) ethylammonium) THF tetrahydrofuran μl microliter X-Phos 5-Bromo-4-chloro-3-indolylphosphate p-Toluidine salt
[00184] Os procedimentos sintéticos representativos para a preparação de compostos da divulgação são esboçados abaixo nos seguintes esquemas. A menos que de outro modo indicado, R1, W1, W2, Y e Z carregam as definições apresentadas acima em conexão com a fórmula (I). Rh é Cl, Br, ou I. Esquema 1 Representative synthetic procedures for preparing compounds of the disclosure are outlined below in the following schemes. Unless otherwise indicated, R1, W1, W2, Y and Z carry the definitions given above in connection with formula (I). Rh is Cl, Br, or I. Scheme 1
[00185] Alguns compostos com estruturas como definidas na Fórmula (I) podem ser preparados por um método geral como ilustrado no Esquema 1. O derivado de nitropiridina (1) é convertido para aminopiridina (2) sob condição redutora tal como hidrogenação na presença de catalisador de Pd/C ou pó de Fe em condições ácidas aquosas. Aminopiridina (2) é depois ligada com cloreto de sulfonila (3) para dar sulfonamida (4) na presença de uma base tal como Na2CO3, Et3N, ou piridina em um solvente aprótico (por exemplo, CH2Cl2, CHCl3, etc.), ou em piridina com uma quantidade catalítica de DMAP, ou sob a condição de Schotten-Baumann. A ligação subsequente da sulfonamida (4) com bis(pinacolato)diboro (5) na presença de um catalisador de Pd apropriado leva ao éster borônico (6).[00185] Some compounds with structures as defined in Formula (I) can be prepared by a general method as illustrated in Scheme 1. The nitropyridine derivative (1) is converted to aminopyridine (2) under reducing condition such as hydrogenation in the presence of Pd/C catalyst or Fe powder under aqueous acidic conditions. Aminopyridine (2) is then coupled with sulfonyl chloride (3) to give the sulfonamide (4) in the presence of a base such as Na2CO3, Et3N, or pyridine in an aprotic solvent (eg, CH2Cl2, CHCl3, etc.), or in pyridine with a catalytic amount of DMAP, or under the Schotten-Baumann condition. Subsequent coupling of the sulfonamide (4) with bis(pinacolato)diboron (5) in the presence of an appropriate Pd catalyst leads to the boronic ester (6).
[00186] A síntese de núcleo heteroaromático (12) tendo um grupo bromo é mostrada no Esquema 1. Bromoarila (7) é primeiro condensado com acetal (8) para fornecer heteroaromático bicíclico (9) em um solvente alcoólico tal como MeOH ou EtOH. A iodação subsequente de (9) com N- iodossuccinimida na temperatura ambiente produz o composto de iodo (10). O composto (10) é depois ligado com acetileno, cianeto ou azida Z (11) para dar o composto heteroaromático (12) sob condições básicas ou na presença de um catalisador de Pd. Os inibidores da cinase desejados tendo a fórmula (14) são obtidos pela ligação de composto heteroaromático de bromo (12) com éster borônico (6) na presença de um catalisador de Pd apropriado. Esquema 2 [00186] The synthesis of heteroaromatic core (12) having a bromine group is shown in Scheme 1. Bromoaryl (7) is first condensed with acetal (8) to provide bicyclic heteroaromatic (9) in an alcoholic solvent such as MeOH or EtOH. Subsequent iodination of (9) with N-iodosuccinimide at room temperature yields the iodine compound (10). Compound (10) is then coupled with acetylene, cyanide or azide Z (11) to give heteroaromatic compound (12) under basic conditions or in the presence of a Pd catalyst. Desired kinase inhibitors having formula (14) are obtained by coupling heteroaromatic bromine compound (12) with boronic ester (6) in the presence of an appropriate Pd catalyst. Scheme 2
[00187] Alternativamente, os compostos aqui divulgados podem ser preparados pelo método como descrito no Esquema 2. O composto de bromo (9) é primeiro ligado com sulfonamida (6) para dar o composto de biarila (15) usando um complexo de Pd apropriado como catalisador. O composto de biarila (15) é depois tratado com um agente de halogenação (tal como NIS) para produzir o composto (16). A ligação do composto (16) com composto (11) (isto é, derivados de acetileno, cianeto ou azida) sob condições básicas ou na presença de um catalisador de Pd produz os inibidores da cinase desejados (14). Esquema 3 Alternatively, the compounds disclosed herein can be prepared by the method as described in Scheme 2. The bromo compound (9) is first coupled with sulfonamide (6) to give the biaryl compound (15) using an appropriate Pd complex as a catalyst. The biaryl compound (15) is then treated with a halogenating agent (such as NIS) to produce compound (16). Coupling of compound (16) with compound (11) (i.e., acetylene, cyanide or azide derivatives) under basic conditions or in the presence of a Pd catalyst produces the desired kinase inhibitors (14). Scheme 3
[00188] O Esquema 3 mostra um outro método para preparar os inibidores da cinase aqui divulgados. Assim, composto de heteroarila substituído (7) tendo um grupo bromo pode reagir com 1,1-dimetóxi- N, N- dimetilmetanamina (17) em uma temperatura elevada para fornecer o intermediário de enamina (18), que é ciclizado ainda com haletos de alquila (19) levando à nitrila (20). A ligação da nitrila (20) com éster borônico (6) na presença de um catalisador de Pd apropriado fornece os inibidores de cinase desejados (21). Esquema 4 Scheme 3 shows another method for preparing the kinase inhibitors disclosed herein. Thus, substituted heteroaryl compound (7) having a bromo group can react with 1,1-dimethoxy-N,N-dimethylmethanamine (17) at an elevated temperature to provide the enamine intermediate (18), which is further cyclized with halides. of alkyl (19) leading to nitrile (20). Linking the nitrile (20) with boronic ester (6) in the presence of an appropriate Pd catalyst provides the desired kinase inhibitors (21). Scheme 4
[00189] Os compostos aqui divulgados também podem ser preparados usando a via sintética como mostrada no Esquema 4. Assim, composto de heteroarila substituído com bromo (7) é primeiro ciclizado com 2- cloroacetaldeído (22) em uma temperatura elevada para dar o composto (9). A ligação do composto (9) com éster borônico (6) na presença de um catalisador de Pd apropriado fornece o composto (23). A iodação do composto (23) com N-iodossuccinimida produz o composto (24). A ligação do composto (24) com o composto (11) (isto é, derivados de acetileno, cianeto ou azida) sob condições básicas ou na presença de um catalisador de Pd produz os inibidores de cinase desejados (14). Esquema 5 [00189] The compounds disclosed herein can also be prepared using the synthetic route as shown in Scheme 4. Thus, bromine substituted heteroaryl compound (7) is first cyclized with 2-chloroacetaldehyde (22) at an elevated temperature to give the compound (9). Coupling of compound (9) with boronic ester (6) in the presence of an appropriate Pd catalyst provides compound (23). Iodination of compound (23) with N-iodosuccinimide yields compound (24). Coupling of compound (24) with compound (11) (i.e., acetylene, cyanide or azide derivatives) under basic conditions or in the presence of a Pd catalyst produces the desired kinase inhibitors (14). Scheme 5
[00190] Alguns compostos com estruturas como definidas na Fórmula (I) também podem ser preparados por um método geral como ilustrado no Esquema 5 acima. O composto (25) é primeiro tratado com hidrato de hidrazina (26) em uma temperatura elevada para fornecer o composto (27), que é subsequentemente ciclizado com dietoximetoxietano (28) levando ao bicíclico heteroaromático (29). A ligação do composto (29) com o éster borônico (6) na presença de um catalisador de Pd apropriado dá o composto (30). A bromação do composto (30) com N-bromossuccinimida produz o composto (31). A ligação do composto (31) com o composto (11) (isto é, derivados de acetileno, cianeto ou azida) sob condições básicas ou na presença de um catalisador de Pd produz os inibidores da cinase desejados (32). EXEMPLOS Exemplo 1 N-(5-(3-etinilimidazo[1,2-b]piridazin-6-il)-2-metoxipiridin-3-il)- 4-fluorobenzenossulfonamida [00190] Some compounds with structures as defined in Formula (I) can also be prepared by a general method as illustrated in Scheme 5 above. Compound (25) is first treated with hydrazine hydrate (26) at an elevated temperature to provide compound (27), which is subsequently cyclized with diethoxymethoxyethane (28) leading to bicyclic heteroaromatic (29). Coupling the compound (29) with the boronic ester (6) in the presence of an appropriate Pd catalyst gives the compound (30). Bromination of compound (30) with N-bromosuccinimide yields compound (31). Coupling of compound (31) with compound (11) (i.e., acetylene, cyanide or azide derivatives) under basic conditions or in the presence of a Pd catalyst produces the desired kinase inhibitors (32). EXAMPLES Example 1 N-(5-(3-ethynimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide
[00191] A uma solução de 6-bromopiridazin-3-amina (3,48 g, 20 mmoles) em EtOH/H2O (5/1, 180 ml) foi adicionado 2-bromo-1,1- dietoxietano (11,8 g, 60 mmoles), seguido pelo ácido p-toluenossulfônico (20,6 mg, 0,12 mmol). A mistura foi agitada a 80 oC por 16 horas e depois concentrada a vácuo. O sólido resultante foi lavado com H2O (4 ml), coletado pela filtração, e secado em uma estufa a vácuo durante a noite a 40 oC para dar o composto do título como um sólido cinza (3,9 g, 100 %). MS (ESI, íon pos.) m/z: 198,1 [M+H]+; RMN1H (400 MHz, CDCl3): h 8,71 (d, J = 9,6 Hz, 1H), 8,44 (d, J = 1,6 Hz, 1H), 8,33 (d, J = 1,9 Hz, 1H), 7,97 (d, J = 9,6Hz, 1H).To a solution of 6-bromopyridazin-3-amine (3.48 g, 20 mmoles) in EtOH/H 2 O (5/1, 180 ml) was added 2-bromo-1,1-diethoxyethane (11.8 g, 60 mmoles), followed by p-toluenesulfonic acid (20.6 mg, 0.12 mmol). The mixture was stirred at 80°C for 16 hours and then concentrated in vacuo. The resulting solid was washed with H 2 O (4 ml), collected by filtration, and dried in a vacuum oven overnight at 40 °C to give the title compound as a gray solid (3.9 g, 100%). MS (ESI, pos. ion) m/z: 198.1 [M+H]+; 1 H-NMR (400 MHz, CDCl3): h 8.71 (d, J = 9.6 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 1 0.9 Hz, 1H), 7.97 (d, J = 9.6Hz, 1H).
[00192] A uma solução de 6-bromoimidazo[1,2-b]piridazina (1,98 g, 10,0 mmol) em metanol (50 ml) a -10 oC foi adicionado N-iodossuccinimida (2,47 g, 11,0 mmoles) em porções. A mistura foi agitada a -10 oC por 30 minutos e depois deixada aquecer até a temperatura ambiente. A reação foi continuada a agitar na temperatura ambiente por 18 horas, e depois concentrada a vácuo. O resíduo foi dissolvido em 100 ml de DCM e lavado com 50 ml de solução aquosa de Na2CO3. A fase orgânica foi concentrada a vácuo para dar o composto do título como um sólido amarelo claro (2,0 g, 61 %). MS (ESI, íon pos.) m/z: 323,9 [M+H]+; RMN1H (400 MHz, CDCl3): h 7,83 (s, 1H), 7,78 (d, J = 9,4 Hz, 1H), 7,21 (d, J = 9,4 Hz, 1H).To a solution of 6-bromoimidazo[1,2-b]pyridazine (1.98 g, 10.0 mmol) in methanol (50 ml) at -10 °C was added N-iodosuccinimide (2.47 g, 11.0 mmoles) in portions. The mixture was stirred at -10°C for 30 minutes and then allowed to warm to room temperature. The reaction was continued to stir at room temperature for 18 hours, then concentrated in vacuo. The residue was dissolved in 100 ml of DCM and washed with 50 ml of aqueous Na2CO3 solution. The organic phase was concentrated in vacuo to give the title compound as a pale yellow solid (2.0 g, 61%). MS (ESI, pos. ion) m/z: 323.9 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 7.83 (s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H).
[00193] A uma suspensão de 6-bromo-3-iodoimidazo[1,2-b]piridazina (1,30 g, 4,0 mmol), etiniltrimetilsilano (0,39 g, 4,0 mmol), Pd(PPh3)2Cl2 (0,28 g, 0,4 mmol) e CuI (0,076 g, 0,4 mmol) em 1,4-dioxano (60 ml) foi adicionado DIPEA (2,6 g, 20,0 mmol). A mistura resultante foi agitada a 90 oC sob atmosfera de N2 por 6 horas e depois concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 3/1) para dar o composto do título como um sólido amarelo (385 mg, 33 %). MS (ESI, íon pos.) m/z: 294,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 7,93 (s, 1H), 7,80 (d, J = 9,4 Hz, 1H), 7,21 (d, J = 9,4 Hz, 1H), 0,32 (s, 9H).[00193] To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (1.30 g, 4.0 mmol), ethynyltrimethylsilane (0.39 g, 4.0 mmol), Pd(PPh3 ) 2 Cl 2 (0.28 g, 0.4 mmol) and CuI (0.076 g, 0.4 mmol) in 1,4-dioxane (60 ml) was added DIPEA (2.6 g, 20.0 mmol). The resulting mixture was stirred at 90°C under N 2 atmosphere for 6 hours and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as a yellow solid (385 mg, 33%). MS (ESI, pos. ion) m/z: 294.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 7.93 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H), 0.32 (s, 9H).
[00194] A uma suspensão de 4-fluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (472,9 mg, 1,17 mmol), 6-bromo-3-((trimetilsilil)etinil)imidazo[1,2-b]piridazina (309,0 mg, 1,1 mmol) e Pd(dppf)Cl2^CH2Cl2 (85,7 mg, 0,11 mmol) em 1,4- dioxano (30 ml) foi adicionada uma solução de Na2CO3 (556,5 mg, 5,25 mmoles) em água (6 ml). A mistura foi agitada a 90 oC sob atmosfera de N2 por 1 hora, depois resfriada até a temperatura ambiente e filtrada. O filtrado foi concentrado a vácuo e o resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 2/1) para dar o composto do título como pó branco (260 mg, 50 %). MS (ESI, íon pos.) m/z: 496,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 8,56 (d, J = 2,2 Hz, 1H), 8,49 (d, J = 2,2 Hz, 1H), 8,02 (d, J = 9,5 Hz, 1H), 8,00 (s, 1H), 7,91 (dd, J = 8,9 Hz, 5,0 Hz, 2H), 7,48 (d, J = 9,5 Hz, 1H), 7,14 (t, J = 8,5 Hz, 2H), 7,00 (s, 1H), 3,93 (s, 3H), 0,33 (s, 9H).To a suspension of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (472.9 mg, 1.17 mmol), 6-bromo-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (309.0 mg, 1.1 mmol) and Pd(dppf)Cl2 ^CH2Cl2 (85.7 mg, 0.11 mmol) in 1,4-dioxane (30 mL) was added a solution of Na2CO3 (556.5 mg, 5.25 mmol) in water (6 mL). The mixture was stirred at 90°C under N2 atmosphere for 1 hour, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as white powder (260 mg, 50%) . MS (ESI, pos. ion) m/z: 496.0 [M+H]+; 1 H-NMR (400 MHz, CDCl3): h 8.56 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 9 .5 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J = 8.9 Hz, 5.0 Hz, 2H), 7.48 (d, J = 9.5 Hz, 1H), 7.14 (t, J = 8.5Hz, 2H), 7.00 (s, 1H), 3.93 (s, 3H), 0.33 (s, 9H).
[00195] A uma solução de 4-fluoro-N-(2-metóxi-5-(3-((trimetilsilil)- etinil)imidazo[1,2-b]piridazin-6-il)piridino-3-il)benzenossulfonamida (180,0 mg, 0,36 mmol) em THF (15 ml) foi adicionado 0,73 ml de TBAF (0,73 mmol, 1,0 M em THF). A mistura resultante foi agitada na temperatura ambiente por 30 minutos e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (PE/EtOAc (v/v) = 1/3) para dar o composto do título como um sólido amarelo claro (74,5 mg, 48 %). MS (ESI, íon pos.) m/z: 424,1 [M+H]+; RMN1H (400 MHz, DMSO-d6): h 8,68 (d, J = 2,2Hz, 1H), 8,31 (d, J = 2,2Hz, 1H), 8,28 (d, J = 9,6 Hz, 1H), 8,14 (s, 1H), 7,95 (d, J = 9,6 Hz, 1H), 7,91 (dd, J = 8,9Hz, 5,2 Hz, 2H), 7,41 (t, J = 8,8Hz, 2H), 5,11 (s, 1H), 3,77 (s, 3H); 13C RMN (100 MHz, DMSO-d6): h 149,2, 142,0, 138,9, 138,5, 136,4, 130,0, 129,9, 129,1, 126,4, 124,4, 121,2, 117,1, 116,5, 116,3, 111,8, 90,1, 70,1, 53,9. Exemplo 2 4-fluoro-N-(5-(3-(3-hidróxiprop-1-in-1-il)imidazo[1,2-b]piridazin- 6-il)-2-metoxipiridin-3-il)benzenossulfonamida [00195] To a solution of 4-fluoro-N-(2-methoxy-5-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl) benzenesulfonamide (180.0 mg, 0.36 mmol) in THF (15 ml) was added 0.73 ml of TBAF (0.73 mmol, 1.0 M in THF). The resulting mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as a pale yellow solid (74.5 mg, 48%). MS (ESI, pos. ion) m/z: 424.1 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 8.68 (d, J = 2.2Hz, 1H), 8.31 (d, J = 2.2Hz, 1H), 8.28 (d, J = 9 0.6 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.91 (dd, J = 8.9Hz, 5.2 Hz, 2H ), 7.41 (t, J = 8.8Hz, 2H), 5.11 (s, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6): h 149.2, 142.0, 138.9, 138.5, 136.4, 130.0, 129.9, 129.1, 126.4, 124, 4, 121.2, 117.1, 116.5, 116.3, 111.8, 90.1, 70.1, 53.9. Example 2 4-fluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl) benzenesulfonamide
[00196] A uma suspensão de 6-bromo-3-iodoimidazo[1,2-b]piridazina (1,48 g, 4,6 mmol), Pd(PPh3)2Cl2 (322 mg, 0,46 mmol), CuI (87 mg, 0,46 mmol) e trietilamina (2,33 g, 23 mmoles) em DMF (65 ml) foi adicionado prop-2-in-1-ol (235 mg, 4,2 mmoles). A mistura foi agitada na temperatura ambiente sob atmosfera de N2 por 4 horas e concentrada a vácuo. O resíduo foi diluído com salmoura (150 ml) e extraído com EtOAc (60 ml x 3). As fases orgânicas combinadas foram secadas em Na2SO4 anidro, e depois concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 4/1) para dar o composto do título como um sólido amarelo (580 mg, 50 %). MS (ESI, íon pos.) m/z: 252,1 [M+H]+.To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (1.48 g, 4.6 mmol), Pd(PPh3)2Cl2 (322 mg, 0.46 mmol), CuI (87mg, 0.46mmol) and triethylamine (2.33g, 23mmol) in DMF (65ml) was added prop-2-yn-1-ol (235mg, 4.2mmol). The mixture was stirred at room temperature under N2 atmosphere for 4 hours and concentrated in vacuo. The residue was diluted with brine (150 ml) and extracted with EtOAc (60 ml x 3). The combined organic phases were dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (580 mg, 50%). MS (ESI, pos. ion) m/z: 252.1 [M+H]+.
[00197] A uma suspensão de 3-(6-bromoimidazo[1,2-b]piridazin-3- il)prop-2-in-1-ol (500 mg, 2 mmoles), 4-fluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (900 mg, 2,2 mmol) e Pd(dppf)ClrCH2Cl2 (164 mg, 0,2 mmol) em DME (40 ml) foi adicionada uma solução de Na2CO3 (530 mg, 5 mmoles) em H2O (4 ml). A mistura foi agitada a 70 oC sob atmosfera de N2 por 4 horas, depois resfriada até a temperatura ambiente, extinta com água (50 ml), e extraída com EtOAc (100 ml x 3). As fases orgânicas combinadas foram lavadas com salmoura (80 ml x 3), secadas em Na2SO4 anidro, e concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 30/1) para dar o composto do título como um sólido amarelo (110 mg, 12 %). MS (ESI, íon pos.) m/z: 454,0 [M+H]+; RMN1H (400 MHz, DMSO-d6): h 3,74 (s, 3H), 4,49 (d, J = 5,9 Hz, 2H), 5,55 (t, J = 5,9 Hz, 1H), 7,42 (t, J = 8,8 Hz, 2H), 7,87-7,92 (m, 3H), 8,09 (s,1H), 8,27 (d, J = 9,6 Hz, 1H), 8,33 (d, J = 2,2 Hz, 1H), 8,68 (d, J = 2,2 Hz, 1H), 10,19 (s, 1H). Exemplo 3 4-fluoro-N-(5-(3-(3-hidroxibut-1-m-1-il)imidazo[1,2-b]piridazm- 6-il)-2-metoxipiridm-3-il)benzenossulfonamida [00197] To a suspension of 3-(6-bromoimidazo[1,2-b]pyridazin-3-yl)prop-2-yn-1-ol (500 mg, 2 mmoles), 4-fluoro-N-( 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (900 mg, 2.2 mmol) and Pd(dppf) ClrCH2Cl2 (164 mg, 0.2 mmol) in DME (40 ml) was added a solution of Na2CO3 (530 mg, 5 mmol) in H2O (4 ml). The mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with water (50 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were washed with brine (80 ml x 3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 30/1) to give the title compound as a yellow solid (110 mg, 12%). MS (ESI, pos. ion) m/z: 454.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 3.74 (s, 3H), 4.49 (d, J = 5.9 Hz, 2H), 5.55 (t, J = 5.9 Hz, 1H ), 7.42 (t, J = 8.8 Hz, 2H), 7.87-7.92 (m, 3H), 8.09 (s, 1H), 8.27 (d, J = 9. 6 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 10.19 (s, 1H). Example 3 4-fluoro-N-(5-(3-(3-hydroxybut-1-m-1-yl)imidazo[1,2-b]pyridazm-6-yl)-2-methoxypyridm-3-yl) benzenesulfonamide
[00198] A uma suspensão de 6-bromo-3-iodoimidazo[1,2-b]piridazina (520 mg, 1,6 mmol), Pd(PPh3)2Cl2 (112 mg, 0,16 mmol), CuI (30 mg, 0,16 mmol) e DIPEA (1,04 g, 4,0 mmoles) em DMF (24 ml) foi adicionado but-3- in-2-ol (112 mg, 1,6 mmol). A mistura resultante foi agitada na temperatura ambiente sob atmosfera de N2 por 2 horas e depois concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (PE/DCM (v/v) = 1/50) para dar o composto do título como um sólido amarelo (210 mg, 50 %). MS (ESI, íon pos.) m/z: 266,0 [M+H]+.To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (520 mg, 1.6 mmol), Pd(PPh3)2Cl2 (112 mg, 0.16 mmol), CuI (30 mg, 0.16 mmol) and DIPEA (1.04 g, 4.0 mmol) in DMF (24 ml) was added but-3-yn-2-ol (112 mg, 1.6 mmol). The resulting mixture was stirred at room temperature under N2 atmosphere for 2 hours and then concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/DCM (v/v) = 1/50) to give the title compound as a yellow solid (210 mg, 50%). MS (ESI, pos. ion) m/z: 266.0 [M+H]+.
[00199] A uma suspensão de 4-fluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (354 mg, 0,87 mmol), 4-(6-bromoimidazo[1,2-b]piridazin-3-il)but-3-in-2-ol (210 mg, 0,79 mmol) e Pd(dppf)ClrCH2Cl2 (58 mg, 0,08 mmol) em DMF (21 ml) foi adicionada uma solução de Na2CO3 (210 mg, 1,97 mmol) em água (4 ml). A mistura foi agitada a 70 oC sob atmosfera de N2 por 4 horas, depois resfriada até a temperatura ambiente, extinta com H2O (100 ml), e extraída com EtOAc (100 ml x 3). As fases orgânicas combinadas foram concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 100/1) para dar o composto do título como um sólido marrom claro (149 mg, 40 %). MS (ESI, íon pos.) m/z: 468,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 10,17 (s, 1H), 8,70-8,69 (d, J = 2,2 Hz, 1H), 8,40-8,39 (d, J = 2,2 Hz, 1H), 8,28-8,26 (d, J = 9,5 Hz, 1H), 8,07 (s, 1H), 7,93-7,86 (m, 3H), 7,43-7,39 (t, J = 8,5 Hz, 2H), 5,67-5,66 (d, J = 5,4 Hz, 1H), 4,79-4,76 (m, 1H), 3,74 (s, 3H), 1,51-1,50 (d, J = 6,6 Hz, 3H). Exemplo 4 4-fluoro-N-(5-(3-(3-hidróxi-3-metilbut-1-m-1-il)imidazo[1,2-b]- piridazm-6-il)-2-metoxipiridm-3-il)benzenossulfonamida To a suspension of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (354 mg, 0.87 mmol), 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)but-3-yn-2-ol (210 mg, 0.79 mmol) and Pd( dppf)ClrCH2Cl2 (58 mg, 0.08 mmol) in DMF (21 ml) was added a solution of Na2CO3 (210 mg, 1.97 mmol) in water (4 ml). The mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with H 2 O (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a light brown solid (149 mg, 40%). MS (ESI, pos. ion) m/z: 468.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.17 (s, 1H), 8.70-8.69 (d, J = 2.2 Hz, 1H), 8.40-8.39 (d, J = 2.2 Hz, 1H), 8.28-8.26 (d, J = 9.5 Hz, 1H), 8.07 (s, 1H), 7.93-7.86 (m, 3H), 7.43-7.39 (t, J = 8.5 Hz, 2H), 5.67-5.66 (d, J = 5.4 Hz, 1H), 4.79-4.76 (m, 1H), 3.74 (s, 3H), 1.51-1.50 (d, J = 6.6 Hz, 3H). Example 4 4-fluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-m-1-yl)imidazo[1,2-b]-pyridazm-6-yl)-2-methoxypyridm -3-yl)benzenesulfonamide
[00200] A uma suspensão de 6-bromo-3-iodoimidazo[1,2-b]piridazina (1,0 g, 3,0 mmoles), Pd(PPh3)2Cl2 (0,2 g, 0,3 mmol), CuI (0,1 g, 0,6 mmol) e trietilamina (1 ml, 6 mmoles) em DMF (15 ml) foi adicionado 2-metilbut-3- in-2-ol (0,25 g, 3 mmoles). A mistura foi agitada na temperatura ambiente sob atmosfera de N2 por 5 horas, depois extinta com H2O (40 ml), e extraída com EtOAc (30 ml x 3). As fases orgânicas combinadas foram lavadas com salmoura (100 ml), secadas em Na2SO4 anidro, e concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 1/1) para dar o composto do título como um sólido amarelo (0,5 g, 58 %). MS (ESI, íon pos.) m/z: 280,0 [M+H]+.[00200] To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (1.0 g, 3.0 mmol), Pd(PPh3)2Cl2 (0.2 g, 0.3 mmol) , CuI (0.1 g, 0.6 mmol) and triethylamine (1 ml, 6 mmol) in DMF (15 ml) was added 2-methylbut-3-yn-2-ol (0.25 g, 3 mmol) . The mixture was stirred at room temperature under N 2 atmosphere for 5 hours, then quenched with H 2 O (40 ml), and extracted with EtOAc (30 ml x 3). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (0.5 g, 58%). MS (ESI, pos. ion) m/z: 280.0 [M+H]+.
[00201] A uma suspensão de 4-(6-bromoimidazo[1,2-b]piridazin-3-il)- 2- metilbut-3-in-2-ol (0,36 g, 1,3 mmol), 4-fluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (0,52 g, 1,3 mmol) e Pd(dppf)Cl2^CH2Cl2 (0,1 g, 0,13 mmol) em DME (20 ml) foi adicionada uma solução de Na2CO3 (0,28 g, 2,6 mmoles) em H2O (1,4 ml). A mistura foi agitada a 100 oC sob atmosfera de N2 durante a noite e depois concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 1/2) para dar o composto do título como um sólido amarelo (0,4 g, 64 %). MS (ESI, íon pos.) m/z: 482,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 10,15 (s, 1H), 8,73 (d, J = 2,1 Hz, 1H), 8,46 (d, J = 2,1 Hz, 1H), 8,28 (d, J = 9,5 Hz, 1H), 8,07 (s, 1H), 7,95 (d, J = 9,5 Hz, 1H), 7,87-7,84 (m, 2H), 7,43-7,39 (m, 2H), 3,73 (s, 3H), 1,58 (s, 6H). Exemplo 5 4-fluoro-N-(2-metóxi-5-(3-(prop-1 -in-1 -il)imidazo[ 1,2- b]piridazin-6-il)piridin-3- il)benzenossulfonamida To a suspension of 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)-2-methylbut-3-yn-2-ol (0.36 g, 1.3 mmol), 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.52 g, 1 0.3 mmol) and Pd(dppf)Cl2^CH2Cl2 (0.1 g, 0.13 mmol) in DME (20 ml) was added a solution of Na2CO3 (0.28 g, 2.6 mmol) in H2O (1 .4 ml). The mixture was stirred at 100°C under a N 2 atmosphere overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a yellow solid (0.4 g, 64%). MS (ESI, pos. ion) m/z: 482.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.15 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.28 (d, J = 9.5 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.87-7.84 (m , 2H), 7.43-7.39 (m, 2H), 3.73 (s, 3H), 1.58 (s, 6H). Example 5 4-fluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3-yl)benzenesulfonamide
[00202] A uma suspensão de 6-bromo-3-iodoimidazo[1,2-b]piridazina (747 mg, 2,31 mmoles), Pd(PPh3)2Cl2 (161,5 mg, 0,23 mmol), CuI (44 mg, 0,23 mmol) e DIPEA (1,49 g, 11,55 mmoles) em DMF (35 ml) foi adicionado Propina (cerca de 3 % em Heptano) (20 ml, 4,44 mmoles). A mistura foi agitada na temperatura ambiente sob atmosfera de N2 por 2 horas, depois extinta com H2O (100 ml), e extraída com EtOAc (100 ml x 3). As fases orgânicas combinadas foram concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (DCM puro) para dar o composto do título como um sólido amarelo (400 mg, 73,6 %). MS (ESI, íon pos.) m/z: 236,0 [M+H]+.To a suspension of 6-bromo-3-iodoimidazo[1,2-b]pyridazine (747 mg, 2.31 mmol), Pd(PPh3)2Cl2 (161.5 mg, 0.23 mmol), CuI (44 mg, 0.23 mmol) and DIPEA (1.49 g, 11.55 mmol) in DMF (35 ml) was added Propine (about 3% in Heptane) (20 ml, 4.44 mmol). The mixture was stirred at room temperature under N 2 atmosphere for 2 hours, then quenched with H 2 O (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by flash silica gel column chromatography (pure DCM) to give the title compound as a yellow solid (400 mg, 73.6%). MS (ESI, pos. ion) m/z: 236.0 [M+H]+.
[00203] A uma suspensão de 6-bromo-3-(prop-1-in-1-il)imidazo[1,2- b]-piridazina (400 mg, 1,70 mmol) em DMF (30 ml) foi adicionado l\](X]ppf)ClyCI I2Cl2 (125 mg, 0,17 mmol). A mistura foi agitada na temperatura ambiente sob atmosfera de N2 por 0,5 hora. Uma solução de 4- fluoro-N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)- benzenossulfonamida (760 mg, 1,86 mmol) em DMF (15 ml) foi adicionado à mistura de reação, seguido pela adição de uma solução de Na2CO3 (450 mg, 4,25 mmol) em H2O (11 ml). A mistura resultante foi agitada a 70 oC sob atmosfera de N2 por 4 horas, depois resfriada até a temperatura ambiente, extinta com H2O (100 ml), e extraída com EtOAc (100 ml x 3). As fases orgânicas combinadas foram concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 200/1) para dar o produto bruto como um sólido marrom. O sólido foi lavado com H2O (10 ml), seguido por EtOH (5 ml) para dar o composto do título como um sólido marrom claro (262 mg, 35,3 %). MS (ESI, íon pos.) m/z: 438,1 [M+H]+; RMN1H (400 MHz, CDCl3): h 10,18 (s, 1H), 8,67 (d, J = 2,2 Hz, 1H), 8,35 (d, J = 2,2 Hz, 1H), 8,24 (d, J = 9,5 Hz, 1H), 8,01 (s, 1H), 7,89-7,86 (m, 3H), 7,41 (t, J = 8,5 Hz, 2H), 3,75 (s, 3H), 2,26 (s, 3H). Exemplo 6 N-(5-(3-cianoimidazo[1,2-b]piridazin-6-il)-2-metoxipiridin-3-il)- 4- fluorobenzenossulfonamida To a suspension of 6-bromo-3-(prop-1-yn-1-yl)imidazo[1,2-b]-pyridazine (400 mg, 1.70 mmol) in DMF (30 ml) was 1\](X]ppf)ClyCl I2Cl2 (125 mg, 0.17 mmol) is added. The mixture was stirred at room temperature under N2 atmosphere for 0.5 hour. A solution of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-benzenesulfonamide (760 mg , 1.86 mmol) in DMF (15 ml) was added to the reaction mixture, followed by the addition of a solution of Na2CO3 (450 mg, 4.25 mmol) in H2O (11 ml). The resulting mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with H 2 O (100 ml), and extracted with EtOAc (100 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 200/1) to give the crude product as a brown solid. The solid was washed with H 2 O (10 ml), followed by EtOH (5 ml) to give the title compound as a light brown solid (262 mg, 35.3%). MS (ESI, pos. ion) m/z: 438.1 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.18 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 9.5 Hz, 1H), 8.01 (s, 1H), 7.89-7.86 (m, 3H), 7.41 (t, J = 8.5 Hz , 2H), 3.75 (s, 3H), 2.26 (s, 3H). Example 6 N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide
[00204] Uma mistura de 6-bromopiridazin-3-amina (1,74 g, 10 mmoles) e 1,1-dimetóxi-N,N-dimetilmetanamina (1,3 g, 11 mmoles) foi agitada a 100 oC por 3 horas. A mistura foi resfriada até a temperatura ambiente e solidificou no repouso. O sólido foi filtrado e secado a vácuo para dar o composto do título como um sólido cinza (1,85 g, 100 %).A mixture of 6-bromopyridazin-3-amine (1.74 g, 10 mmoles) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.3 g, 11 mmoles) was stirred at 100°C for 3 hours. The mixture was cooled to room temperature and solidified on standing. The solid was filtered and dried in vacuo to give the title compound as a gray solid (1.85 g, 100%).
[00205] A uma solução de NÓ-(6-bromopiridazin-3-il)-N,N-dimetil- formimidamida (1,23 g, 5,41 mmol) em acetonitrila (15 ml) foi adicionada bromoacetonitrila (1,13 ml, 16,25 mmoles). A mistura foi agitada a 80 oC durante a noite e depois concentrada a vácuo. O resíduo foi dissolvido em uma mistura de acetonitrila (15 ml) e DIPEA (6,0 ml, 35,60 mmoles). A mistura resultante foi agitada na temperatura ambiente por 4 horas e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (PE/EtOAc (v/v) = 2/1) para dar o composto do título como um sólido amarelo (0,9 g, 75 %). MS (ESI, íon pos.) m/z: 222,0 [M+H]+; RMN1H (400 MHz, CDCl3): h8,22 (s, 1H), 7,95 (d, J = 7,7 Hz, 1H), 7,43 (d, J = 9,5 Hz, 1H).To a solution of NO-(6-bromopyridazin-3-yl)-N,N-dimethyl-formimidamide (1.23 g, 5.41 mmol) in acetonitrile (15 ml) was added bromoacetonitrile (1.13 ml, 16.25 mmoles). The mixture was stirred at 80°C overnight and then concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile (15 ml) and DIPEA (6.0 ml, 35.60 mmoles). The resulting mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a yellow solid (0.9 g, 75%). MS (ESI, pos. ion) m/z: 222.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.22 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 9.5 Hz, 1H).
[00206] A uma mistura de 4-fluoro-N-(2-metóxi-5-(4,4,5,5-tetrametil- 1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (612 mg, 1,5 mmol), 6-bromoimidazo[1,2-b]piridazina-3-carbonitrila (222 mg, 1,0 mmol), Pd(dppf)Cl2^CH2Cl2 (81,6 mg, 0,1 mmol) e Na2CO3 (424 mg, 4,0 mmoles) foram adicionados 1,4-dioxano (25 ml) e água (5 ml). A mistura foi agitada a 90 oC sob atmosfera de N2 por 5 horas, depois resfriada até a temperatura ambiente e filtrada. O filtrado foi concentrado a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 1/2) para dar o composto do título como um sólido amarelo claro (400 mg, 94 %). MS (ESI, íon pos.) m/z: 425,0 [M+H]+; RMN1H (400 MHz, DMSO-d6): h 3,80 (s, 3H), 7,41-7,48 (m, 2H), 7,89-7,97 (m, 2 H), 8,16 (d, J = 9,7 Hz, 1H), 8,30 (d, J = 2,2 Hz, 1H), 8,46 (d, J = 9. 6 Hz, 1H), 8,61 (s, 1H), 8,72(d, J = 2,2 Hz, 1H). Exemplo 7 N-(2-cloro-5-(3-etimlimidazo[1,2-b]piridazm-6-il)piridm-3-il)-4- fluorobenzenossulfonamida To a mixture of 4-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (612 mg, 1.5 mmol), 6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile (222 mg, 1.0 mmol), Pd(dppf)Cl2^CH2Cl2 (81.6 mg, 0, 1 mmol) and Na 2 CO 3 (424 mg, 4.0 mmol) were added 1,4-dioxane (25 ml) and water (5 ml). The mixture was stirred at 90°C under a N2 atmosphere for 5 hours, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a pale yellow solid (400 mg, 94%). MS (ESI, pos. ion) m/z: 425.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 3.80 (s, 3H), 7.41-7.48 (m, 2H), 7.89-7.97 (m, 2H), 8.16 (d, J = 9.7 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.46 (d, J = 9. 6 Hz, 1H), 8.61 (s , 1H), 8.72(d, J = 2.2 Hz, 1H). Example 7 N-(2-chloro-5-(3-ethylimidazo[1,2-b]pyridazm-6-yl)pyridm-3-yl)-4-fluorobenzenesulfonamide
[00207] A uma mistura do ácido (6-cloro-5-(4-fluorofenilsulfonamido)- piridin-3-il)borônico (521,0 mg, 1,58 mmol), 6-bromo-3-((trimetilsilil)etinil)- imidazo[1,2-b]piridazina (370,0 mg, 1,26 mmol), Pd(dppf)Cl2<H2Cl2 (71 mg, 0,087 mmol) e Na2CO3 (433 mg, 4,1 mmoles) em 1,4-dioxano (20 ml) foi adicionado água (4 ml). A mistura foi agitada a 90 oC sob atmosfera de N2 por 1 hora, depois resfriada até a temperatura ambiente, e filtrada. O filtrado foi concentrado a vácuo e o resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 1/1) para dar o composto do título como pó branco (110 mg, 11,5 %). MS (ESI, íon pos.) m/z: 500,0 [M+H]+.To a mixture of (6-chloro-5-(4-fluorophenylsulfonamido)-pyridin-3-yl)boronic acid (521.0 mg, 1.58 mmol), 6-bromo-3-((trimethylsilyl) ethynyl)-imidazo[1,2-b]pyridazine (370.0 mg, 1.26 mmol), Pd(dppf)Cl2<H2Cl2 (71 mg, 0.087 mmol) and Na2CO3 (433 mg, 4.1 mmol) in 1,4-dioxane (20 ml) was added to water (4 ml). The mixture was stirred at 90°C under N2 atmosphere for 1 hour, then cooled to room temperature, and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as white powder (110 mg, 11.5 %). MS (ESI, pos. ion) m/z: 500.0 [M+H]+.
[00208] A uma solução de N-(2-cloro-5-(3- ((trimetilsilil)etinil)imidazo-[1,2-b]piridazin-6-il)piridin-3-il)-4- fluorobenzenossulfonamida (250,0 mg, 0,5 mmol) em THF (20 ml) foi adicionado 1 ml de TBAF (1 mmol, 1,0 M em THF). A mistura resultante foi agitada na temperatura ambiente por 1 hora, depois concentrada a vácuo. O resíduo foi purificado por uma HPLC preparativa para dar o composto do título como um sólido amarelo claro (80 mg, 37,6 %). MS (ESI, íon pos.) m/z: 428,0 [M+H]+; RMN1H (400 MHz, DMSO-d6): h 5,11 (s, 1H), 7,42-7,48 (t, J = 8,7 Hz, 2H), 7,87-7,91 (m, 2H), 8,00-8,03 (d, J =9,6 Hz, 1H), 8,19 (s, 1H), 8,35-8,42 (m, 2H), 8,95 (s, 1H), 10,65 (s, 1H). Exemplo 8 N-(5-(3-etinilimidazo[1,2-b]piridazin-6-il)-2-metoxipiridin-3-il)- 2,4- difluorobenzenossulfonamida To a solution of N-(2-chloro-5-(3-((trimethylsilyl)ethynyl)imidazo-[1,2-b]pyridazin-6-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (250.0 mg, 0.5 mmol) in THF (20 ml) was added 1 ml of TBAF (1 mmol, 1.0 M in THF). The resulting mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a pale yellow solid (80 mg, 37.6%). MS (ESI, pos. ion) m/z: 428.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 5.11 (s, 1H), 7.42-7.48 (t, J = 8.7 Hz, 2H), 7.87-7.91 (m, 2H), 8.00-8.03 (d, J =9.6 Hz, 1H), 8.19 (s, 1H), 8.35-8.42 (m, 2H), 8.95 (s , 1H), 10.65 (s, 1H). Example 8 N-(5-(3-ethynimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
[00209] A uma mistura de 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (349,0 mg, 0,82 mmol), 6-bromo-3-((trimetilsilil)etinil)imidazo[1,2-b]piridazina (200,0 mg, 0,64 mmol), Pd(dppf)Cl2^CH2Cl2 (55,6 mg, 0,064 mmol) e Na2CO3 (338,8 mg, 3,196 mmoles) em 1,4-dioxano (18 ml) foi adicionada água (3 ml). A mistura foi agitada a 90 oC sob atmosfera de N2 por 1 hora, depois resfriada até a temperatura ambiente, e filtrada. O filtrado foi concentrado a vácuo e o resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 1/1) para dar o composto do título como um sólido branco (160 mg, 46 %). MS (ESI, íon pos.) m/z: 514,0 [M+H]+.To a mixture of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl )benzenesulfonamide (349.0 mg, 0.82 mmol), 6-bromo-3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (200.0 mg, 0.64 mmol), Pd(dppf )Cl 2 ·CH 2 Cl 2 (55.6 mg, 0.064 mmol) and Na 2 CO 3 (338.8 mg, 3.196 mmol) in 1,4-dioxane (18 ml) was added to water (3 ml). The mixture was stirred at 90°C under N2 atmosphere for 1 hour, then cooled to room temperature, and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white solid (160 mg, 46% ). MS (ESI, pos. ion) m/z: 514.0 [M+H]+.
[00210] A uma solução de 2,4-difluoro-N-(2-metóxi-5-(3- ((trimetilsilil)-etinil)imidazo[1,2-b]piridazin-6-il)piridin-3- il)benzenossulfonamida (230,0 mg, 0,45 mmol) em THF (20 ml) foi adicionado 0,9 ml de TBAF (0,9 mmol, 1,0 M em THF). A solução foi agitada na temperatura ambiente por 30 minutos, depois concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (PE/EtOAc (v/v) = 1/3) para dar o composto do título como um sólido branco (100 mg, 51 %). MS (ESI, íon pos.) m/z: 442,1 [M+H]+; RMN1H (400 MHz, DMSO-d6): h 3,73 (s, 3H), 5,05 (s, 1H), 7,20-7,24 (t, J = 8,7 Hz, 1H), 7,56-7,60 (t, J = 8. 6 Hz, 1H), 7,78-7,84 (q, J =8,3 Hz, 1H), 7,947,96 (d, J = 9,6 Hz, 1H), 8,13 (s, 1H), 8,28-8,30 (m, 2H), 8,73-8,74 (d, J = 2,0 Hz, 1H). Exemplo 9 2,4-difluoro-N-(5-(3-(3-hidróxiprop-1-in-1-il)imidazo[1,2-b]- piridazin-6-il)-2-metoxipiridin-3-il)benzenossulfonamida To a solution of 2,4-difluoro-N-(2-methoxy-5-(3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)pyridin-3- yl)benzenesulfonamide (230.0 mg, 0.45 mmol) in THF (20 ml) was added 0.9 ml of TBAF (0.9 mmol, 1.0 M in THF). The solution was stirred at room temperature for 30 minutes, then concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as a white solid (100 mg, 51%). MS (ESI, pos. ion) m/z: 442.1 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 3.73 (s, 3H), 5.05 (s, 1H), 7.20-7.24 (t, J = 8.7 Hz, 1H), 7 .56-7.60 (t, J = 8. 6Hz, 1H), 7.78-7.84 (q, J =8.3 Hz, 1H), 7.947.96 (d, J = 9.6 Hz, 1H), 8.13 (s, 1H), 8.28-8.30 (m, 2H), 8.73-8.74 (d, J = 2.0 Hz, 1H). Example 9 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-b]-pyridazin-6-yl)-2-methoxypyridin-3 -yl)benzenesulfonamide
[00211] A uma suspensão de 3-(6-bromoimidazo[1,2-b]piridazin-3- il)prop-2-in-1-ol (1,69 g, 6,72 mmol) e Pd(PPh3)2Cl2^CH2Cl2 (549 mg, 0,672 mmol) em DME (70 ml) foi adicionada uma solução de Na2CO3 (1,78 g, 16,8 mmol) em água (20 ml), seguida pela adição de uma solução de 2,4-difluoro- N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)- benzenossulfonamida (3,15 g, 7,39 mmoles) em DME (100 ml). A mistura resultante foi agitada a 75 oC sob atmosfera de N2 por 4 horas, depois resfriada até a temperatura ambiente, extinta com água (300 ml), e extraída com EtOAc (200 ml x 4). As fases orgânicas combinadas foram secadas em Na2SO4 e concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (PE/EtOAc (v/v) = 5/1) para dar o composto do título como um sólido amarelo (1,3 g, 42 %). MS (ESI, íon pos.) m/z: 472,0 [M+H]+; RMN1H (400 MHz, DMSO-d6): h 10,43 (s, 1H), 8,74-8,73 (d, J = 2,2 Hz, 1H), 8,30-8,27 (m, 2H), 8,06 (s, 1H), 7,92-7,90 (d, J = 9,5 Hz, 1H), 7,83-7,77 (m, 1H), 7,60-7,54 (m, 1H), 7,24-7,19 (m, 1H), 5,53-5,51 (m, 1H), 4,50-4,48 (d, J = 5,6 Hz, 1H), 3,72 (s, 3H). Exemplo 10 2,4-difluoro-N-(5-(3-(3-hidroxibut-1-in-1-il)imidazo[1,2-b]- piridazm-6-il)-2-metoxipiridm-3-il)benzenossulfonamida To a suspension of 3-(6-bromoimidazo[1,2-b]pyridazin-3-yl)prop-2-yn-1-ol (1.69 g, 6.72 mmol) and Pd(PPh3 )2Cl2^CH2Cl2 (549 mg, 0.672 mmol) in DME (70 ml) was added a solution of Na2CO3 (1.78 g, 16.8 mmol) in water (20 ml), followed by the addition of a solution of 2, 4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-benzenesulfonamide (3.15 g, 7.39 mmoles) in DME (100 ml). The resulting mixture was stirred at 75°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with water (300 ml), and extracted with EtOAc (200 ml x 4). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (1.3 g, 42%). MS (ESI, pos. ion) m/z: 472.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 10.43 (s, 1H), 8.74-8.73 (d, J = 2.2 Hz, 1H), 8.30-8.27 (m, 2H), 8.06 (s, 1H), 7.92-7.90 (d, J = 9.5 Hz, 1H), 7.83-7.77 (m, 1H), 7.60-7 .54 (m, 1H), 7.24-7.19 (m, 1H), 5.53-5.51 (m, 1H), 4.50-4.48 (d, J = 5.6 Hz , 1H), 3.72 (s, 3H). Example 10 2,4-difluoro-N-(5-(3-(3-hydroxybut-1-yn-1-yl)imidazo[1,2-b]-pyridazm-6-yl)-2-methoxypyridm-3 -yl)benzenesulfonamide
[00212] A uma suspensão de 4-(6-bromoimidazo[1,2-b]piridazin-3- il)but-3-in-2-ol (400 mg, 1,50 mmol), PdCdppfCVCHiCli (123 mg, 0,15 mmol) e 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2- il)-piridino-3-il)benzenossulfonamida (705 mg, 1,65 mmol) em DME (41 ml) foi adicionada uma solução de Na2CO3 (398 mg, 3,76 mmoles) em água (6 ml). A mistura foi agitada a 75 oC sob atmosfera de N2 por 3,5 horas, depois resfriada até a temperatura ambiente, extinta com H2O (200 ml), e extraída com EtOAc (200 ml x 4). As camadas orgânicas combinadas foram concentradas a vácuo e o resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 1/1) para dar o composto do título como um sólido amarelo (300 mg, 41 %). MS (ESI, íon pos.) m/z: 486,0 [M+H]+; RMN1H (400 MHz, DMSO-d6): h 10,41 (s, 1H), 8,75-8,74 (d, J = 2,2 Hz, 1H), 8,36-8,35 (d, J = 2,2 Hz, 1H), 8,28-8,26 (d, J = 9,5 Hz, 1H), 8,06 (s, 1H), 7,93-7,91 (d, J = 9,5 Hz, 1H), 7,82-7,68 (m, 1H), 7,59-7,54 (m, 1H), 7,237,18 (m, 1H), 5,65-5,64 (d, J = 5,4 Hz, 1H), 4,80-4,74 (m, 1H), 3,72 (s, 3H), 1,50-1,49 (d, J = 6,6 Hz, 3H). Exemplo 11 2,4-difluoro-N-(5-(3-(3-hidróxi-3-metilbut-1-in-1-il)imidazo[1,2- b]piridazm-6-il)-2-metoxipiridm-3-il)benzenossulfonamida [00212] To a suspension of 4-(6-bromoimidazo[1,2-b]pyridazin-3-yl)but-3-yn-2-ol (400 mg, 1.50 mmol), PdCdppfCVCHiCli (123 mg, 0.15 mmol) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine-3-yl )benzenesulfonamide (705mg, 1.65mmol) in DME (41ml) was added a solution of Na 2 CO 3 (398mg, 3.76mmol) in water (6ml). The mixture was stirred at 75°C under N 2 atmosphere for 3.5 hours, then cooled to room temperature, quenched with H 2 O (200 ml), and extracted with EtOAc (200 ml x 4). The combined organic layers were concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (300 mg, 41 %). MS (ESI, pos. ion) m/z: 486.0 [M+H]+; 1 H-NMR (400 MHz, DMSO-d6): h 10.41 (s, 1H), 8.75-8.74 (d, J = 2.2 Hz, 1H), 8.36-8.35 (d, J = 2.2 Hz, 1H), 8.28-8.26 (d, J = 9.5 Hz, 1H), 8.06 (s, 1H), 7.93-7.91 (d, J = 9.5Hz, 1H), 7.82-7.68 (m, 1H), 7.59-7.54 (m, 1H), 7.237.18 (m, 1H), 5.65-5, 64 (d, J = 5.4 Hz, 1H), 4.80-4.74 (m, 1H), 3.72 (s, 3H), 1.50-1.49 (d, J = 6. 6Hz, 3H). Example 11 2,4-difluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-b]pyridazm-6-yl)-2- methoxypyridm-3-yl)benzenesulfonamide
[00213] A uma mistura de 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (2,13 g, 5,0 mmoles), 6-bromoimidazo[1,2-b]piridazina (1 g, 0,79 mmol), Pd(dppf)ClrCH2Cl2 (408 mg, 0,5 mmol) e Na2CO3 (1,32 g, 12,5 mmoles) foram adicionados DME (120 ml) e água (30 ml). A mistura foi agitada a 70 oC sob atmosfera de N2 por 4 horas, depois resfriada até a temperatura ambiente, extinta com H2O (500 ml), e depois extraída com EtOAc (500 ml x 3). As fases orgânicas combinadas foram concentradas a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 200/3) para dar o composto do título como um sólido marrom claro (1,28 g, 61,4 %). MS (ESI, íon pos.) m/z: 418,0 [M+H]+.To a mixture of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl )benzenesulfonamide (2.13 g, 5.0 mmoles), 6-bromoimidazo[1,2-b]pyridazine (1 g, 0.79 mmol), Pd(dppf)ClrCH2Cl2 (408 mg, 0.5 mmol) and Na2CO3 (1.32 g, 12.5 mmol) was added DME (120 ml) and water (30 ml). The mixture was stirred at 70°C under N 2 atmosphere for 4 hours, then cooled to room temperature, quenched with H 2 O (500 ml), and then extracted with EtOAc (500 ml x 3). The combined organic phases were concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 200/3) to give the title compound as a light brown solid (1.28 g, 61.4%). MS (ESI, pos. ion) m/z: 418.0 [M+H]+.
[00214] A uma solução de 2,4-difluoro-N-(5-(imidazo[1,2-b]piridazin- 6-il)-2-metoxipiridin-3-il)benzenossulfonamida (1,28 g, 3,07 mmoles) em DMF (30 ml) foi adicionado NBS (545,8 mg, 3,07 mmoles) em porções. A reação foi agitada a -20 oC por 12 horas e depois extinta com H2O (100 ml). A mistura foi continuada a agitar durante a noite e depois filtrada. O sólido foi coletado e purificado por uma HPLC preparativa para dar o composto do título como um sólido amarelo claro (320 mg, 21 %). MS (ESI, íon pos.) m/z: 496,1 [M+H]+.To a solution of 2,4-difluoro-N-(5-(imidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.28 g, 3 .07 mmoles) in DMF (30 ml) was added NBS (545.8 mg, 3.07 mmoles) in portions. The reaction was stirred at -20°C for 12 hours and then quenched with H2O (100 ml). The mixture was continued to stir overnight and then filtered. The solid was collected and purified by preparative HPLC to give the title compound as a pale yellow solid (320 mg, 21 %). MS (ESI, pos. ion) m/z: 496.1 [M+H]+.
[00215] A uma suspensão de N-(5-(3-bromoimidazo[1,2-b]piridazin-6- il)-2-metoxipiridin-3-il)-2,4-difluorobenzenossulfonamida (100 mg, 0,21 mmol), Pd(PPh3)2Cl2 (15 mg, 0,02 mmol), CuI (4 mg, 0,02 mmol) e DIPEA (67 mg, 0,52 mmol) em DMF (2 ml) foi adicionado 2-metilbut-3-in-2-ol (53 mg, 0,63 mmol). A mistura foi agitada na temperatura ambiente sob atmosfera de N2 por 6 horas e depois concentrada a vácuo. O resíduo foi purificado por uma HPLC preparativa para dar o composto do título como um sólido amarelo (36 mg, 35 %). MS (ESI, íon pos.) m/z: 500,5 [M+H]+; RMN1H (400 MHz, CDCl3): h 8,59-8,58 (d, J = 2,2 Hz, 1H), 8,46-8,45 (d, J = 2,2 Hz, 1H), 8,00-7,94 (m, 3H), 7,47 (s, 1H), 6,96-6,90 (m, 2H), 4,01 (s, 3H), 3,18(s, 1H), 2,97 (s, 1H), 1,57 (s, 6H). Exemplo 12 4-fluoro-N-(5-(3-(3-hidróxi-3-metilbut-1-in-1-il)-[1,2,4]triazolo [4,3-b]piridazm-6-il)-2-metoxipiridm-3-il)benzenossulfonamida To a suspension of N-(5-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (100mg, 0, 21 mmol), Pd(PPh3)2Cl2 (15 mg, 0.02 mmol), CuI (4 mg, 0.02 mmol) and DIPEA (67 mg, 0.52 mmol) in DMF (2 ml) was added 2- methylbut-3-yn-2-ol (53 mg, 0.63 mmol). The mixture was stirred at room temperature under N2 atmosphere for 6 hours and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a yellow solid (36 mg, 35%). MS (ESI, pos. ion) m/z: 500.5 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.59-8.58 (d, J = 2.2 Hz, 1H), 8.46-8.45 (d, J = 2.2 Hz, 1H), 8 .00-7.94 (m, 3H), 7.47 (s, 1H), 6.96-6.90 (m, 2H), 4.01 (s, 3H), 3.18(s, 1H) ), 2.97 (s, 1H), 1.57 (s, 6H). Example 12 4-fluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)-[1,2,4]triazolo[4,3-b]pyridazm-6 -yl)-2-methoxypyridin-3-yl)benzenesulfonamide
[00216] Uma mistura de 3,6-dicloropiridazina (4,5 g, 30,4 mmoles), cloridreto de hidrazinocarboxamida (6,7 g, 60,8 mmoles) e três gotas de HCl conc. em EtOH (30 ml) foi selada em um frasco de microondas e aquecida em um microondas a 120 oC por 1 hora. A mistura foi depois resfriada até a temperatura ambiente e concentrada a vácuo. O resíduo foi lavado com H2O (15 ml) e Et2O (20 ml), depois filtrado, e a torta do filtro foi secada a vácuo para dar o composto do título como um sólido amarelo (1,8 g, 32 %). MS (ESI, íon pos.) m/z: 171,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 7,89 (d, J = 9,8 Hz, 1H), 7,20 (d, J = 9,8 Hz, 1H).A mixture of 3,6-dichloropyridazine (4.5 g, 30.4 mmol), hydrazinecarboxamide hydrochloride (6.7 g, 60.8 mmol) and three drops of conc. in EtOH (30 ml) was sealed in a microwave flask and heated in a microwave at 120 oC for 1 hour. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was washed with H 2 O (15 ml) and Et 2 O (20 ml), then filtered, and the filter cake was dried in vacuo to give the title compound as a yellow solid (1.8 g, 32%). MS (ESI, pos. ion) m/z: 171.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 7.89 (d, J = 9.8 Hz, 1H), 7.20 (d, J = 9.8 Hz, 1H).
[00217] Uma mistura de 6-cloro-[1,2,4]triazolo[4,3-b]piridazin-3-ol (1,8 g, 10,6 mmoles) e PCl5 (0,4 g, 2 mmoles) em POCl3 (20 ml) foi agitada a 120 oC por 12 horas e concentrada a vácuo. O resíduo foi extinta com água gelada (50 ml) a 0 oC. A mistura resultante foi extraída com EtOAc (50 ml x 2). As fases orgânicas combinadas foram lavadas com salmoura (100 ml), secadas em Na2SO4 anidro, e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 3/1) para dar o composto do título como um sólido amarelo claro (0,5 g, 20 %). MS (ESI, íon pos.) m/z: 189,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 8,08 (d, J = 9,7 Hz, 1H), 8,73 (d, J = 9,7 Hz, 1H).[00217] A mixture of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ol (1.8 g, 10.6 mmoles) and PCl5 (0.4 g, 2 mmoles) in POCl3 (20 ml) was stirred at 120°C for 12 hours and concentrated in vacuo. The residue was quenched with ice water (50 ml) at 0°C. The resulting mixture was extracted with EtOAc (50 ml x 2). The combined organic phases were washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/1) to give the title compound as a pale yellow solid (0.5 g, 20%). MS (ESI, pos. ion) m/z: 189.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.08 (d, J = 9.7 Hz, 1H), 8.73 (d, J = 9.7 Hz, 1H).
[00218] A uma suspensão de 3,6-dicloro-[1,2,4]triazolo[4,3- b]piridazina (0,5 g, 1,8 mmol), 4-fluoro-N-(2-metóxi-5-(4,4,5,5-tetrametil- 1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (0,8 g, 2,2 mmoles) e Pd(dppf)Cl2^CH2Cl2 (0,15 g, 0,18 mmol) em DME (20 ml) foi adicionada uma solução de Cs2CO3 (1,2 g, 3,6 mmol) em H2O (2 ml). A mistura resultante foi agitada a 70 oC sob atmosfera de N2 por 12 horas e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 1/2) para dar o composto do título como um sólido amarelo claro (0,5 g, 64 %). MS (ESI, íon pos.) m/z: 435,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 10,20 (s, 1H), 8,71 (d, J = 2,2 Hz, 1H), 8,46 (d, J = 9,8 Hz, 1H), 8,27 (d, J = 2,2 Hz, 1H), 8,04 (d, J = 9,8 Hz, 1H), 7,90-7,87 (m, 2H), 7,42-7,38 (m, 2H), 3,79 (s, 3H).[00218] To a suspension of 3,6-dichloro-[1,2,4]triazolo[4,3-b]pyridazine (0.5 g, 1.8 mmol), 4-fluoro-N-(2- methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.8 g, 2.2 mmol) and Pd(dppf) Cl2^CH2Cl2 (0.15g, 0.18mmol) in DME (20ml) was added a solution of Cs2CO3 (1.2g, 3.6mmol) in H2O (2ml). The resulting mixture was stirred at 70°C under N 2 atmosphere for 12 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a pale yellow solid (0.5 g, 64%). MS (ESI, pos. ion) m/z: 435.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.20 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.46 (d, J = 9.8 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 9.8 Hz, 1H), 7.90-7.87 (m, 2H), 7.42-7 .38 (m, 2H), 3.79 (s, 3H).
[00219] Uma mistura de N-(5-(3-cloro-[1,2,4]triazolo[4,3-b]piridazin- 6-il)-2- metoxipiridin-3-il)-4-fluorobenzenossulfonamida (0,4 g, 0,96 mmol), 2-metilbut-3-in-2-ol (0,16 g, 0,2 mmol), Pd2(dba)3 (0,04 g, 0,04 mmol), CuI (0,04 g, 0,16 mmol), i-Pr2NH (0,29 g, 2,88 mmoles) e X-Phos (0,09 g, 0,16 mmol) em DMF (20 ml) foi agitada a 100 oC sob atmosfera N2 por 36 horas. A mistura foi depois concentrada a vácuo e o resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH = 50/1) para dar o composto do título como um sólido amarelo (0,3 g, 68 %). MS (ESI, íon pos.) m/z: 483,0 [M+H]+; RMN1H (400 MHz, CDCl3): h 10,20 (s, 1H), 8,75 (d, J = 2,2 Hz, 1H), 8,51 (d, J = 9,8 Hz, 1H), 8,44 (d, J = 2,2 Hz, 1H), 8,06 (d, J = 9,8 Hz, 1H), 7,87-7,84 (m, 2H), 7,43-7,38 (m, 2H), 3,75 (s, 3H), 1,60 (s, 6H). Exemplo 13 2,4-difluoro-N-(2-metóxi-5-(3-(prop-1-in-1-il)imidazo[1,2-b]- piridazin-6-il)piridin-3-il)benzenossulfonamida [00219] A mixture of N-(5-(3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide (0.4 g, 0.96 mmol), 2-methylbut-3-yn-2-ol (0.16 g, 0.2 mmol), Pd2(dba)3 (0.04 g, 0.04 mmol) ), CuI (0.04 g, 0.16 mmol), i-Pr2NH (0.29 g, 2.88 mmol) and X-Phos (0.09 g, 0.16 mmol) in DMF (20 ml) was stirred at 100°C under N2 atmosphere for 36 hours. The mixture was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH = 50/1) to give the title compound as a yellow solid (0.3 g, 68%). MS (ESI, pos. ion) m/z: 483.0 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 10.20 (s, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 9.8 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 9.8 Hz, 1H), 7.87-7.84 (m, 2H), 7.43-7 .38 (m, 2H), 3.75 (s, 3H), 1.60 (s, 6H). Example 13 2,4-difluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-b]-pyridazin-6-yl)pyridin-3- il)benzenesulfonamide
[00220] A uma suspensão de 6-cloro-3-iodoimidazo[1,2-b]piridazina (3 g, 10,7 mmoles), Pd(PPh3)2Cl2 (750 mg, 1,07 mmol), CuI (200 mg, 1,07 mmol), e diisopropiletilamina (7,5 ml, 53,5 mmoles) em 107 ml de DMF foi adicionado Propine (cerca de 3 % em Heptano, 60 ml, 21,4 mmoles). A mistura foi agitada na temperatura ambiente sob atmosfera de N2 por 4 horas, depois H2O (300 ml) foi adicionada e a mistura resultante foi extraída com EtOAc (300 ml x 3). As fases orgânicas combinadas foram secadas em Na2SO4 anidro e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM puro) para fornecer o composto do título como um sólido amarelo (560 mg, 27 %). MS (ESI, íon pos.) m/z: 192,3 [M+H]+.[00220] To a suspension of 6-chloro-3-iodoimidazo[1,2-b]pyridazine (3 g, 10.7 mmoles), Pd(PPh3)2Cl2 (750 mg, 1.07 mmol), CuI (200 mg, 1.07 mmol), and diisopropylethylamine (7.5 ml, 53.5 mmol) in 107 ml of DMF was added Propine (about 3% in Heptane, 60 ml, 21.4 mmol). The mixture was stirred at room temperature under N 2 atmosphere for 4 hours, then H 2 O (300 ml) was added and the resulting mixture was extracted with EtOAc (300 ml x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (pure DCM) to furnish the title compound as a yellow solid (560 mg, 27%). MS (ESI, pos. ion) m/z: 192.3 [M+H]+.
[00221] A uma suspensão de 6-cloro-3-(prop-1-in-1-il)imidazo[1,2-b]- piridazina (560 mg, 2,9 mmoles), 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (1,5 g, 3,5 mmoles) e Pd(dppf)Cl2<H2Cl2 (237 mg, 0,29 mmol) em 1,4-dioxano/ H2O (30 ml/6 ml) foi adicionado Na2CO3 (774 mg, 7,3 mmoles). A mistura resultante foi purgada com N2 por três vezes e agitada a 90 oC selada sob atmosfera de N2 por 5 horas, depois resfriada até a temperatura ambiente e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 100/1) para dar o composto do título como um sólido amarelo claro (700 mg, 53 %). MS (ESI, íon pos.) m/z: 455,9 [M+H]+; Pureza: 97,6 %; RMN1H (600 MHz, DMSO-d6): h 10,46 (s, 1H), 8,73 (d, J = 2,0 Hz, 1H), 8,31 (d, J = 2,2 Hz, 1H), 8,26 (d, J = 9,5 Hz, 1H), 8,01 (s, 1H), 7,89 (d, J = 9,5 Hz, 1H), 7,79 (d, J = 6,3 Hz, 1H), 7,58 (d, J = 8,7 Hz, 1H), 7,22 (td, J = 8,5, 2,2 Hz, 1H), 3,72 (s, 3H), 2,25 (s, 3H). Exemplo 14 N-(5-(3-cianoimidazo[1,2-b]piridazin-6-il)-2-metoxipiridin-3-il) ciclopropanossulfonamida [00221] To a suspension of 6-chloro-3-(prop-1-in-1-yl)imidazo[1,2-b]-pyridazine (560 mg, 2.9 mmoles), 2,4-difluoro- N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (1.5 g, 3.5 mmoles) and Pd(dppf)Cl2<H2Cl2 (237 mg, 0.29 mmol) in 1,4-dioxane/H2O (30 ml/6 ml) was added Na2CO3 (774 mg, 7.3 mmol). The resulting mixture was purged with N2 three times and stirred at 90°C sealed under N2 atmosphere for 5 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a pale yellow solid (700 mg, 53%). MS (ESI, pos. ion) m/z: 455.9 [M+H]+; Purity: 97.6%; 1 H-NMR (600 MHz, DMSO-d6): h 10.46 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H ), 8.26 (d, J = 9.5 Hz, 1H), 8.01 (s, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.79 (d, J = 6.3 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.22 (td, J = 8.5, 2.2 Hz, 1H), 3.72 (s , 3H), 2.25 (s, 3H). Example 14 N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide
[00222] A um solvente resfriado de MeOH (50,0 ml) foi adicionado Na (2,90 g, 126,4 mmoles) às porções, depois a mistura foi aquecida até a temperatura ambiente e agitada até que o Na fosse todo dissolvido, depois a solução foi adicionada a uma suspensão de 5-bromo-2-cloro-3-nitropiridina (10,0 g, 42,12 mmoles, Shanghai long sheng hua gong, China) em MeOH (100 ml) a 0 oC. A mistura de reação foi agitada a 0 oC por 1 hora, depois aquecida até a temperatura ambiente e agitada ainda por 16 horas, depois concentrada para 80 ml e extinta com água (100 ml). O precipitado foi filtrado, lavado com água (50 ml x 2) e secado sob luz infravermelha para dar o composto do título como um sólido amarelo claro (9,62 g, 98 %). MS (ESI, íon pos.) m/z: 233,0 [M+H]+.To a cooled solvent of MeOH (50.0 ml) was added Na (2.90 g, 126.4 mmoles) in portions, then the mixture was warmed to room temperature and stirred until the Na was all dissolved. , then the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (10.0 g, 42.12 mmoles, Shanghai long sheng hua gong, China) in MeOH (100 ml) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for a further 16 hours, then concentrated to 80 ml and quenched with water (100 ml). The precipitate was filtered, washed with water (50 ml x 2) and dried under infrared light to give the title compound as a pale yellow solid (9.62 g, 98%). MS (ESI, pos. ion) m/z: 233.0 [M+H]+.
[00223] A uma suspensão de 5-bromo-2-metóxi-3-nitropiridina (9,62 g, 41,3 mmoles) em etanol (100 ml) e água (10 ml) foi adicionado pó de Ferro (9,25 g, 165,2 mmoles, Tianjin guangfukeji) e NH4Cl (8,83 g, 165,2 mmoles). A mistura foi aquecida ao refluxo e agitada ainda por 15 horas, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi dissolvido em 250 ml de EtOAc e a solução resultante foi lavada com solução saturada aquosa de bicarbonato de sódio (100 ml), água (100 ml x 2) e salmoura (150 ml), secada em Na2SO4 anidro, e concentrada a vácuo para dar o composto do título como um sólido amarelo (8,16 g, 97 %). MS (ESI, íon pos.) m/z: 202,8 [M+H]+.[00223] To a suspension of 5-bromo-2-methoxy-3-nitropyridine (9.62 g, 41.3 mmoles) in ethanol (100 ml) and water (10 ml) was added Iron powder (9.25 g, 165.2 mmoles, Tianjin guangfukeji) and NH 4 Cl (8.83 g, 165.2 mmoles). The mixture was heated to reflux and stirred for a further 15 hours, then cooled to room temperature, and concentrated in vacuo. The residue was dissolved in 250 ml of EtOAc and the resulting solution was washed with saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml x 2) and brine (150 ml), dried over anhydrous Na2SO4, and concentrated to vacuum to give the title compound as a yellow solid (8.16 g, 97%). MS (ESI, pos. ion) m/z: 202.8 [M+H]+.
[00224] A uma suspensão de 5-bromo-2-metoxipiridin-3-amina (200 mg, 0,99 mmol) em piridina (10 ml) foi adicionado cloreto de ciclopropano- sulfonila (346 mg, 2,46 mmoles) lentamente. A reação foi agitada na temperatura ambiente por 18 horas, depois aquecida a 60 oC e agitada por 5 horas. A mistura foi resfriada até a temperatura ambiente, depois acidificada ao pH = 2 com HCl 1 M (aq.), e a mistura resultante foi extraída com DCM (15 ml x 3). As camadas orgânicas combinadas foram lavadas com água (20 ml x 2) e salmoura (20 ml), secadas em Na2SO4 anidro, e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc(v/v) = 5/1) para dar o composto do título como um sólido amarelo (191 mg, 63 %). MS (ESI, íon pos.) m/z: 306,9 [M+H]+; RMN1H (600 MHz, CDCl3): h 7,96 (d, J = 2,22 Hz, 1H), 7,92 (d, J = 2,22 Hz, 1H), 6,70 (brs, 1H), 4,00 (s, 3H), 2,56-2,47 (m, 1H), 1,26-1,20 (m, 2H), 1,040,97 (m, 2H).To a suspension of 5-bromo-2-methoxypyridin-3-amine (200mg, 0.99mmol) in pyridine (10ml) was added cyclopropanesulfonyl chloride (346mg, 2.46mmol) slowly . The reaction was stirred at room temperature for 18 hours, then heated to 60°C and stirred for 5 hours. The mixture was cooled to room temperature, then acidified to pH = 2 with 1 M HCl (aq.), and the resulting mixture was extracted with DCM (15 ml x 3). The combined organic layers were washed with water (20 ml x 2) and brine (20 ml), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc(v/v) = 5/1) to give the title compound as a yellow solid (191 mg, 63%). MS (ESI, pos. ion) m/z: 306.9 [M+H]+; 1 H-NMR (600 MHz, CDCl3): h 7.96 (d, J = 2.22 Hz, 1H), 7.92 (d, J = 2.22 Hz, 1H), 6.70 (brs, 1H), 4.00 (s, 3H), 2.56-2.47 (m, 1H), 1.26-1.20 (m, 2H), 1.040.97 (m, 2H).
[00225] Uma solução de N-(5-bromo-2-metoxipiridin-3- il)ciclopropano-sulfonamida (50 mg, 0,163 mmol), 4,4,4Ó,4Ó,5,5,5Ó,5Ó- octametil-2,2Ó-bi(1,3,2-dioxaborolano) (166 mg, 0,652 mmol, Beijing datianfengtuo) e KOAc (64 mg, 0,652 mmol) em 1,4-dioxano (10 ml) foi desgaseificado e carregado com N2 por 3 vezes, depois l\](clppf)Cl:<I bCb (27 mg, 0,0326 mmol, matthey) foi adicionado. A mistura foi aquecida a 80 oC e agitada ainda por 2,5 horas, depois resfriada até a temperatura ambiente, concentrada a vácuo e o resíduo foi dissolvido em DCM (20 ml). A mistura resultante foi filtrada através de uma almofada de CELITE®. O filtrado foi lavado com água (15 ml x 3) e salmoura (15 ml), secado em Na2SO4 anidro, e concentrado a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (lE/EtOAc (v/v) = 5/2) para dar o composto do título como um sólido branco (50 mg, 86 %). MS (ESI, íon pos.) m/z: 355,1 [M+I]+; RMN1I (600 MIz, CDCl3): h 8,30 (d, J = 1,65 Iz, 1I), 8,08 (d, J = 1,65 Iz, 1I), 6,64 (brs, 1I), 4,03 (s, 3I), 2,60-2,40 (m, 1I), 1,33 (s, 12I), 1,22-1,15 (m, 2I), 0,99-0,93 (m, 2I).A solution of N-(5-bromo-2-methoxypyridin-3-yl)cyclopropanesulfonamide (50 mg, 0.163 mmol), 4,4,4O,4O,5,5,5O,5O-octamethyl- 2,2O-bi(1,3,2-dioxaborolane) (166mg, 0.652mmol, Beijing datianfengtuo) and KOAc (64mg, 0.652mmol) in 1,4-dioxane (10ml) was degassed and charged with N 2 per 3 times, then 1\](clppf)Cl:<I bCb (27 mg, 0.0326 mmol, matthey) was added. The mixture was heated to 80°C and stirred for a further 2.5 hours, then cooled to room temperature, concentrated in vacuo and the residue dissolved in DCM (20 ml). The resulting mixture was filtered through a pad of CELITE®. The filtrate was washed with water (15 ml x 3) and brine (15 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1E/EtOAc (v/v) = 5/2) to give the title compound as a white solid (50 mg, 86%). MS (ESI, pos. ion) m/z: 355.1 [M+I]+; 1 I NMR (600 MIz, CDCl3): h 8.30 (d, J = 1.65 Iz, 1I), 8.08 (d, J = 1.65 Iz, 1I), 6.64 (brs, 1I), 4.03 (s, 3I), 2.60-2.40 (m, 1I), 1.33 (s, 12I), 1.22-1.15 (m, 2I), 0.99-0, 93 (m, 2I).
[00226] A uma solução de 6-bromoimidazo[1,2-b]piridazina-3- carbonitrila (50 mg, 0,23 mmol) em 1,4-dioxano (10 ml) foram adicionados N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)ciclo- propanossulfonamida (88 mg, 0,25 mmol), Na2CO3 (48 mg, 0,46 mmol), H2O (2 ml) e l\](dppf)Cl:^CI hCl: (37 mg, 0,046 mmol). A mistura foi aquecida até 80 oC e agitada ainda por 1 hora, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi extraído com DCM (10 ml x 3). As fases orgânicas combinadas foram secadas em Na2SO4 anidro, e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (DCM/MeOH (v/v) = 200/1) para dar o composto do título como um sólido rosa claro (60 mg, 72 %). MS (ESI, íon pos.) m/z: 371,0 [M+H]+; RMN1H (600 MHz, CDCl3): h 8,60 (d, J = 2,4 Hz, 1H), 8,40 (d, J = 2,1 Hz, 1H), 8,27 (s, 1H), 8,16 (d, J = 9,6 Hz, 1H), 7,70 (d, J = 9,9 Hz, 1H), 6,85 (brs, 1H), 4,14 (s, 3H), 2,63-2,57 (m, 1H), 1,36-1,25 (s, 2H), 1,14-1,09 (m, 2H). Exemplo 15 2,4-difluoro-N-(5-(3-(3-hidróxiprop-1-in-1-il)imidazo[1,2- um]piridin-6-il)-2- metoxipiridin-3-il)benzenossulfonamida To a solution of 6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile (50 mg, 0.23 mmol) in 1,4-dioxane (10 ml) was added N-(2-methoxy- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)cyclopropanesulfonamide (88mg, 0.25mmol), Na2CO3 (48mg, 0 .46 mmol), H 2 O (2 ml) and el 1 ](dppf)Cl 2 Cl 2 Cl hCl: (37 mg, 0.046 mmol). The mixture was heated to 80°C and stirred for a further 1 hour, then cooled to room temperature, and concentrated in vacuo. The residue was extracted with DCM (10 ml x 3). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v) = 200/1) to give the title compound as a pale pink solid (60 mg, 72%). MS (ESI, pos. ion) m/z: 371.0 [M+H]+; 1 H-NMR (600 MHz, CDCl3): h 8.60 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J = 9.6 Hz, 1H), 7.70 (d, J = 9.9 Hz, 1H), 6.85 (brs, 1H), 4.14 (s, 3H), 2.63-2.57 (m, 1H), 1.36-1.25 (s, 2H), 1.14-1.09 (m, 2H). Example 15 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-um]pyridin-6-yl)-2-methoxypyridin-3- il)benzenesulfonamide
[00227] A uma solução de 5-bromopiridin-2-amina (10,0 g, 57,7 mmoles) em EtOH/H2O (100 ml/20 ml) foi adicionado 2-cloroacetaldeído (10,5 g, 86,7 mmoles) lentamente. A mistura foi aquecida a 80 oC e agitada ainda por 15 horas, depois resfriada até a temperatura ambiente e concentrada a vácuo. A solução saturada aquosa de NaHCO3 (200 ml) foi adicionada ao resíduo. A mistura resultante foi extraída com DCM (200 ml x 3). As fases orgânicas combinadas foram concentradas a vácuo para dar o composto do título como um sólido marrom (11,3 g, 100 %). MS (ESI, íon pos.) m/z: 197,1 [M+H]+.[00227] To a solution of 5-bromopyridin-2-amine (10.0 g, 57.7 mmoles) in EtOH/H2O (100 ml/20 ml) was added 2-chloroacetaldehyde (10.5 g, 86.7 mmoles) slowly. The mixture was heated to 80°C and stirred for a further 15 hours, then cooled to room temperature and concentrated in vacuo. A saturated aqueous solution of NaHCO3 (200 ml) was added to the residue. The resulting mixture was extracted with DCM (200 ml x 3). The combined organic phases were concentrated in vacuo to give the title compound as a brown solid (11.3 g, 100%). MS (ESI, pos. ion) m/z: 197.1 [M+H]+.
[00228] Uma mistura de 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5- tetrametil-1,3,2-dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (23,8 g, 55,2 mmoles), 6-bromoimidazo[1,2-b]piridazina (10,0 g, 50,8 mmol), Pd(dppf)Cl2^CH2Cl2 (4,15g, 5,1 mmol) e N2CO3 (13,2 g, 127,5 mmol) em DME (250 ml) e água (50 ml) foi desgaseificada e carregada com N2 por 3 vezes. A mistura foi aquecida a 70 oC e agitada por 6 horas, depois resfriada até a temperatura ambiente, filtrada através de uma almofada de CELITE®, e o filtrado foi concentrado a vácuo. O resíduo foi purificado por uma cromatografia em coluna de sílica (EtOAc puro) para dar o composto do título como um sólido branco (15,1 g, 70,4 %). MS (ESI, íon pos.) m/z: 417,0 [M+H]+.A mixture of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl) benzenesulfonamide (23.8 g, 55.2 mmoles), 6-bromoimidazo[1,2-b]pyridazine (10.0 g, 50.8 mmol), Pd(dppf)Cl2^CH2Cl2 (4.15g, 5, 1 mmol) and N 2 CO 3 (13.2 g, 127.5 mmol) in DME (250 ml) and water (50 ml) was degassed and charged with N 2 3 times. The mixture was heated to 70°C and stirred for 6 hours, then cooled to room temperature, filtered through a pad of CELITE®, and the filtrate concentrated in vacuo. The residue was purified by a silica column chromatography (pure EtOAc) to give the title compound as a white solid (15.1 g, 70.4%). MS (ESI, pos. ion) m/z: 417.0 [M+H]+.
[00229] A uma solução de 2,4-difluoro-N-(5-(imidazo[1,2-a]piridin-6- il)-2-metoxipiridin-3-il)benzenossulfonamida (12,7 g, 30,5 mmoles) em DMF (130 ml) foi adicionado NIS (17,2 g, 30,5 mmoles) lentamente. A mistura foi agitada a 45 oC por 6 horas, depois H2O (150 ml) foi adicionada e agitada na temperatura ambiente por mais 1 hora. Filtrada e a torta do filtro foi lavada com EtOAc (20 ml) para dar o composto do título como um sólido branco (15,4 g, 90 %). MS (ESI, íon pos.) m/z: 543,0 [M+H]+.[00229] To a solution of 2,4-difluoro-N-(5-(imidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (12.7 g, 30 .5 mmoles) in DMF (130 ml) was added NIS (17.2 g, 30.5 mmoles) slowly. The mixture was stirred at 45°C for 6 hours, then H 2 O (150 ml) was added and stirred at room temperature for a further 1 hour. Filtered and the filter cake washed with EtOAc (20 ml) to give the title compound as a white solid (15.4 g, 90%). MS (ESI, pos. ion) m/z: 543.0 [M+H]+.
[00230] A uma suspensão de 2,4-difluoro-N-(5-(3-iodoimidazo[1,2- a]piridin-6-il)-2-metoxipiridino-3-il)benzenossulfonamida (15,0 g, 27,6 mmoles), Pd(PPh3)2Cl2 (2,0 g, 2,9 mmoles), CuI (0,55 g, 2,8 mmoles) e Et3N (14,0 g, 137,5 mmoles) em 70 ml de DMF foi adicionado prop-2-in-1-ol (5,6 g, 99,6 mmoles). A mistura foi agitada a 50 oC sob atmosfera de N2 por 6 horas, depois resfriada até a temperatura ambiente, filtrada e o filtrado foi concentrado a vácuo. H2O (100 ml) foi adicionado ao resíduo e a mistura resultante foi filtrada. A torta do filtro foi purificada por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 50/1) para dar o produto bruto, depois o produto bruto foi lavado com EtOAc/MeOH (20 ml/10 ml) para dar o composto do título como um sólido amarelo (6,7 g, 50,4 %). MS (ESI, íon pos.) m/z: 471,0[M+H]+; RMN1H (600 MHz, DMSO-d6): h 10,36 (s, 1H), 8,62 (s, 1H), 8,41 (d, J = 2,2 Hz, 1H), 7,98 (d, J = 2,3 Hz, 1H), 7,83-7,71 (m, 1H), 7,87-7,50 (m, 3H), 7,687,50 (m, 1H), 7,22 (td, J = 8,5, 2,2 Hz, 1H), 5,48 (t, J = 5,9 Hz, 1H), 4,50 (d, J = 5,8 Hz, 2H), 3,66 (s, 3H). Exemplo 16 2,4-difluoro-N-(5-(3-(3-hidroxibut-1-in-1-il)imidazo[1,2-a]- piridin-6-il)-2- metoxipiridm-3-il)benzenossulfonamida [00230] To a suspension of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (15.0 g) , 27.6 mmoles), Pd(PPh3)2Cl2 (2.0 g, 2.9 mmoles), CuI (0.55 g, 2.8 mmoles) and Et3N (14.0 g, 137.5 mmoles) in 70 ml of DMF was added prop-2-yn-1-ol (5.6 g, 99.6 mmol). The mixture was stirred at 50 °C under N2 atmosphere for 6 hours, then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. H2O (100 ml) was added to the residue and the resulting mixture was filtered. The filter cake was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the crude product, then the crude product was washed with EtOAc/MeOH (20 ml/10) ml) to give the title compound as a yellow solid (6.7 g, 50.4%). MS (ESI, pos. ion) m/z: 471.0[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.36 (s, 1H), 8.62 (s, 1H), 8.41 (d, J = 2.2 Hz, 1H), 7.98 (d , J = 2.3 Hz, 1H), 7.83-7.71 (m, 1H), 7.87-7.50 (m, 3H), 7.687.50 (m, 1H), 7.22 ( td, J = 8.5, 2.2 Hz, 1H), 5.48 (t, J = 5.9 Hz, 1H), 4.50 (d, J = 5.8 Hz, 2H), 3, 66 (s, 3H). Example 16 2,4-difluoro-N-(5-(3-(3-hydroxybut-1-yn-1-yl)imidazo[1,2-a]-pyridin-6-yl)-2-methoxypyridm-3 -yl)benzenesulfonamide
[00231] A uma suspensão de 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]- piridin-6-il)-2-metoxipiridino-3-il)benzenossulfonamida (1,5 g, 2,7 mmoles), Pd(PPh3)2Cl2 (0,2 g, 0,3 mmol), CuI (0,06 g, 0,3 mmol) e Et3N (1,4 g, 13,5 mmoles) em 7 ml de DMF foi adicionado but-3-in-2-ol (0,7 g, 9,9 mmoles). A mistura foi agitada a 50 oC sob atmosfera de N2 por 6 horas, depois resfriada até a temperatura ambiente, filtrada e o filtrado foi concentrado a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 50/1) para dar o composto do título como um sólido amarelo (0,5 g, 40,1 %). MS (ESI, íon pos.) m/z: 485,1 [M+H]+; RMN1H (600 MHz, CDCl3): h 8,39 (s, 1H), 8,10 (d, J = 1,9 Hz, 1H), 7,97 (t, J = 13,6 Hz, 1H), 7,90 (dd, J = 14,4, 8,3 Hz, 1H), 7,84 (s, 1H), 7,47 (d, J = 3,5 Hz, 1H), 7,37 (s, 1H), 6,97 (dt, J = 15,8, 8,2 Hz, 2H), 4,93 (q, J = 6,6 Hz, 1H), 4,03 (s, 3H), 3,49 (s, 1H), 1,65 (d, J = 6,6 Hz, 3H). Exemplo 17 2,4-difluoro-N-(5-(3-(3-hidróxi-3-metilbut-1-in-1-il)imidazo[1,2- a]piridm-6-il)-2-metoxipiridm-3-il)benzenossulfonamida [00231] To a suspension of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]-pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.5 g, 2.7 mmol), Pd(PPh3)2Cl2 (0.2 g, 0.3 mmol), CuI (0.06 g, 0.3 mmol) and Et3N (1.4 g, 13.5 mmol) in 7 ml of DMF was added but-3-yn-2-ol (0.7 g, 9.9 mmoles). The mixture was stirred at 50 °C under N2 atmosphere for 6 hours, then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.5 g, 40.1%). MS (ESI, pos. ion) m/z: 485.1 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 8.39 (s, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.97 (t, J = 13.6 Hz, 1H), 7.90 (dd, J = 14.4, 8.3 Hz, 1H), 7.84 (s, 1H), 7.47 (d, J = 3.5 Hz, 1H), 7.37 (s , 1H), 6.97 (dt, J = 15.8, 8.2 Hz, 2H), 4.93 (q, J = 6.6 Hz, 1H), 4.03 (s, 3H), 3 .49 (s, 1H), 1.65 (d, J = 6.6 Hz, 3H). Example 17 2,4-difluoro-N-(5-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-a]pyridm-6-yl)-2- methoxypyridm-3-yl)benzenesulfonamide
[00232] A uma suspensão de 2,4-difluoro-N-(5-(3-iodoimidazo[1,2- a]piridin-6-il)-2- metoxipiridino-3-il)benzenossulfonamida (1,5 g, 2,7 mmoles), Pd(PPh3)2Cl2 (0,2 g, 0,3 mmol), CuI (0,06 g, 0,3 mmol) e Et3N (1,4g, 13,5 mmoles) em 7 ml de DMF foi adicionado 2-metilbut-3-in-2-ol (0,8 g, 9,9 mmoles). A mistura foi agitada a 50 oC sob atmosfera de N2 por 6 horas, depois resfriada até a temperatura ambiente, filtrada e o filtrado foi concentrado a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 50/1) para dar o composto do título como um sólido amarelo (0,6 g, 40 %). MS (ESI, íon pos.) m/z: 499,1 [M+H]+; RMN1H (600 MHz, DMSO-d6): h 10,38 (s, 1H), 8,52 (d, J = 0,7 Hz, 1H), 8,41 (d, J = 2,3 Hz, 1H), 7,97 (d, J = 2,3 Hz, 1H), 7,90 (s, 1H), 7,81-7,74 (m, 2H), 7,67 (dd, J = 9,3, 1,8 Hz, 1H), 7,61-7,56 (m, 1H), 7,22 (td, J = 8,5, 2,3 Hz, 1H), 5,71 (s, 1H), 3,68 (s, 3H), 1,57 (s, 6H). Exemplo 18 2,4-difluoro-N-(2-metóxi-5-(3-(prop-1-in-1-il)imidazo[1,2-a]- piridin-6-il)piridin-3-il)benzenossulfonamida To a suspension of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.5 g , 2.7mmol), Pd(PPh3)2Cl2 (0.2g, 0.3mmol), CuI (0.06g, 0.3mmol) and Et3N (1.4g, 13.5mmol) in 7 ml of DMF was added 2-methylbut-3-yn-2-ol (0.8 g, 9.9 mmoles). The mixture was stirred at 50 °C under N2 atmosphere for 6 hours, then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.6 g, 40%). MS (ESI, pos. ion) m/z: 499.1 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.38 (s, 1H), 8.52 (d, J = 0.7 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H ), 7.97 (d, J = 2.3 Hz, 1H), 7.90 (s, 1H), 7.81-7.74 (m, 2H), 7.67 (dd, J = 9. 3, 1.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.22 (td, J = 8.5, 2.3 Hz, 1H), 5.71 (s, 1H ), 3.68 (s, 3H), 1.57 (s, 6H). Example 18 2,4-difluoro-N-(2-methoxy-5-(3-(prop-1-yn-1-yl)imidazo[1,2-a]-pyridin-6-yl)pyridin-3- il)benzenesulfonamide
[00233] A uma mistura de 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]- piridin-6-il)-2-metoxipiridino-3-il)benzenossulfonamida (1,50 g, 2,76 mmoles), Pd(PPh3)2Cl2 (0,189 g, 0,27 mmol) e CuI (52 mg, 0,27 mmol) em 20 ml de DMF foi adicionada diisopropiletilamina (1,78 g, 13,8 mmoles). A mistura foi desgaseificada e carregada com nitrogênio por três vezes, depois propine (0,44 g, 11,04 mmoles) foi adicionado por uma seringa. A mistura resultante foi agitada a 45 oC sob atmosfera de N2 por 10 horas, e concentrada a vácuo. H2O (40 ml) foi adicionada e a mistura resultante foi agitada na temperatura ambiente por 1 hora, filtrada e a torta do filtro foi purificada por uma cromatografia em coluna de gel de sílica cintilante (DCM/MeOH (v/v) = 300/1) para dar o composto do título como um sólido amarelo (220 mg, 17,52 %). MS (ESI, íon pos.) m/z: 454,9 [M+H]+; RMN1H (600 MHz, DMSO-d6): h 10,46 (s, 1H), 9,18 (d, J = 7,3 Hz, 1H), 8,86 (s, 1H), 8,41 (s, 1H), 8,34 (s, 1H), 7,78 (dd, J = 14,6, 8,0 Hz, 1H), 7,72 (d, J = 7,3 Hz, 1H), 7,58 (t, J = 9,1 Hz, 1H), 7,21 (t, J = 7,6 Hz, 1H), 3,71 (s, 3H), 2,14 (s, 3H). Exemplo 19 N-(5-(3-cianoimidazo[1,2-a]piridin-6-il)-2-metoxipiridin-3-il)- 2,4- difluorobenzenossulfonamida To a mixture of 2,4-difluoro-N-(5-(3-iodoimidazo[1,2-a]-pyridin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (1.50 g, 2.76 mmol), Pd(PPh3)2Cl2 (0.189 g, 0.27 mmol) and CuI (52 mg, 0.27 mmol) in 20 ml DMF was added diisopropylethylamine (1.78 g, 13.8 mmoles). The mixture was degassed and charged with nitrogen three times, then propine (0.44 g, 11.04 mmoles) was added via syringe. The resulting mixture was stirred at 45°C under N 2 atmosphere for 10 hours, and concentrated in vacuo. H2O (40 ml) was added and the resulting mixture was stirred at room temperature for 1 hour, filtered and the filter cake was purified by scintillating silica gel column chromatography (DCM/MeOH (v/v) = 300/ 1) to give the title compound as a yellow solid (220 mg, 17.52%). MS (ESI, pos. ion) m/z: 454.9 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.46 (s, 1H), 9.18 (d, J = 7.3 Hz, 1H), 8.86 (s, 1H), 8.41 (s , 1H), 8.34 (s, 1H), 7.78 (dd, J = 14.6, 8.0 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7 .58 (t, J = 9.1 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 3.71 (s, 3H), 2.14 (s, 3H). Example 19 N-(5-(3-cyanoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
[00234] Uma mistura de 5-cloropiridin-2-amina (1,29 g, 10 mmoles) e Dimetóxi-N,N-dimetilmetanamina (1,31 g, 11 mmoles) foi agitada a 100 oC por 3 horas, depois resfriada até a temperatura ambiente, e um sólido amarelo foi formado na solução homogênea. Filtrada, e a torta do filtro foi secada a vácuo para dar o composto do título como um sólido amarelo (1,85 g, 100 %), o produto bruto foi usado na etapa seguinte sem outra purificação. MS (ESI, íon pos.) m/z: 184,0 [M+H]+.A mixture of 5-chloropyridin-2-amine (1.29 g, 10 mmoles) and Dimethoxy-N,N-dimethylmethanamine (1.31 g, 11 mmoles) was stirred at 100°C for 3 hours, then cooled to room temperature, and a yellow solid formed in the homogeneous solution. Filtered, and the filter cake dried in vacuo to give the title compound as a yellow solid (1.85 g, 100%), the crude product was used in the next step without further purification. MS (ESI, pos. ion) m/z: 184.0 [M+H]+.
[00235] A uma solução de NÓ-(5-cloropiridin-2-il)-N,N-dimetil- formimidamida (1,83 g, 10 mmoles) em acetonitrila (30 ml) foi adicionado bromoacetonitrila (3,6 g, 30 mmoles). A reação foi agitada a 80 oC durante a noite, depois resfriada até a temperatura ambiente, e diisopropiletilamina (12,0 ml, 70 mmoles) foi adicionada. A mistura resultante foi agitada na temperatura ambiente por 4 horas e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (DCM puro) para dar o composto do título como um sólido amarelo (0,9 g, 51 %). MS (ESI, íon pos.) m/z: 178,0 [M+H]+.To a solution of NO-(5-chloropyridin-2-yl)-N,N-dimethyl-formimidamide (1.83 g, 10 mmoles) in acetonitrile (30 ml) was added bromoacetonitrile (3.6 g, 30 mmoles). The reaction was stirred at 80 °C overnight, then cooled to room temperature, and diisopropylethylamine (12.0 ml, 70 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (pure DCM) to give the title compound as a yellow solid (0.9 g, 51%). MS (ESI, pos. ion) m/z: 178.0 [M+H]+.
[00236] Uma mistura de 6-cloroimidazo[1,2-a]piridino-3-carbonitrila (900 g, 5,07 mmoles), 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (3,24 g, 7,06 mmoles), PdCdppfCirCHiCh (416 mg, 0,51 mmol) e \a2CO3 (2,15 g, 20,28 mmoles) foi desgaseificado e carregado com N2 por 3 vezes, seguido pela adição de 1,4-dioxano (125 ml) e água (25 ml). A mistura foi desgaseificada e carregada com N2 por 3 vezes, depois aquecida a 90 oC e agitada ainda por 6 horas. Depois de resfriar até a temperatura ambiente, a mistura foi filtrada e o filtrado foi concentrado a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) =2/1) para dar o composto do título como um sólido marrom claro (280 mg, 12 %). MS (ESI, íon pos.) m/z: 442,1 [M+H]+; RMN1H (400 MHz, CDCl3): h 8,39 (s, 1H), 8,24 (s, 1H), 8,11 (s, 1H), 7,95 (q, J = 8,7 Hz, 3H), 7,63 (d, J = 9,0 Hz, 1H), 7,38 (s, 1H), 7,04 (t, J = 8,1 Hz, 1H), 6,99 (t, J = 9,2 Hz, 1H), 4,02 (s, 3H). Exemplo 20 N-(5-(3-(3-hidroxiprop-1-in-1-il)imidazo[1,2-a]piridin-6-il)-2- metoxipiridin-3-il)ciclopropanossulfonamida [00236] A mixture of 6-chloroimidazo[1,2-a]pyridine-3-carbonitrile (900 g, 5.07 mmoles), 2,4-difluoro-N-(2-methoxy-5-(4,4) ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (3.24 g, 7.06 mmoles), PdCdppfCirCHiCh (416 mg, 0.51 mmol) and \ a2CO3 (2.15 g, 20.28 mmoles) was degassed and charged with N2 3 times, followed by the addition of 1,4-dioxane (125 ml) and water (25 ml). The mixture was degassed and charged with N2 3 times, then heated to 90°C and stirred for a further 6 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =2/1) to give the title compound as a light brown solid (280 mg, 12%). MS (ESI, pos. ion) m/z: 442.1 [M+H]+; 1 H-NMR (400 MHz, CDCl 3 ): h 8.39 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.95 (q, J = 8.7 Hz, 3H ), 7.63 (d, J = 9.0 Hz, 1H), 7.38 (s, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.99 (t, J = 9.2 Hz, 1H), 4.02 (s, 3H). Example 20 N-(5-(3-(3-hydroxyprop-1-yn-1-yl)imidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide
[00237] A uma solução de 6-bromoimidazo[1,2-a]piridina (318 mg, 1,61 mmol) em 1,4-dioxano (15 ml) foram adicionados N-(2-metóxi-5- (4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)piridin-3- il)ciclopropanossulfonamida (600 mg, 1,69 mmol), KOAc (316 mg, 3,22 mmoles), H2O (3 ml) e Pd(dppf)Cl2^CH2Cl2 (131 mg, 0,161 mmol). A reação foi aquecida a 85 oC e agitada ainda por 5 horas sob atmosfera de N2, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi dissolvido em DCM (200 ml) e a mistura resultante foi filtrada através de um CELITE®. O filtrado foi lavado com H2O (100 ml) e salmoura (100 ml). As camadas aquosas combinadas foram extraídas com DCM (50 ml x 3). Os extratos orgânicos combinados foram secados em Na2SO4 anidro, e concentrados a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (DCM/MeOH (v/v) = 65/1) para dar o composto do título como um sólido amarelado (342 mg, 62 %). MS (ESI, íon pos.) m/z: 345,0 [M+H]+; RMN1H (600 MHz, DMSO-d6): h 9,42 (s, 1H), 8,91 (s, 1H), 8,35 (d, J = 2,1 Hz, 1H), 7,99 (s, 1H), 7,93 (d, J = 2,4 Hz, 1H), 7,68-7,61 (m, 2H), 7,54 (dd, J = 1,8, 9,6 Hz, 1H), 3,98 (s, 3H), 2,82-2,74 (m, 1H), 1,00-0,89 (m, 4H).To a solution of 6-bromoimidazo[1,2-a]pyridine (318 mg, 1.61 mmol) in 1,4-dioxane (15 ml) was added N-(2-methoxy-5- (4') ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)cyclopropanesulfonamide (600mg, 1.69mmol), KOAc (316mg, 3.22mmol), H2O (3 ml) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (131 mg, 0.161 mmol). The reaction was heated to 85°C and stirred for a further 5 hours under a N2 atmosphere, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (200 ml) and the resulting mixture was filtered through a CELITE®. The filtrate was washed with H2O (100 ml) and brine (100 ml). The combined aqueous layers were extracted with DCM (50 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v) = 65/1) to give the title compound as a yellowish solid (342 mg, 62%). MS (ESI, pos. ion) m/z: 345.0 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 9.42 (s, 1H), 8.91 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.99 (s , 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.54 (dd, J = 1.8, 9.6 Hz, 1H), 3.98 (s, 3H), 2.82-2.74 (m, 1H), 1.00-0.89 (m, 4H).
[00238] A uma solução de N-(5-(imidazo[1,2-a]piridin-6-il)-2-metóxi- piridin-3-il)ciclopropanossulfonamida (292 mg, 0,85 mmol) em acetonitrila (20 ml) foi adicionado NIS (210 mg, 0,933 mmol) a 0 oC. A mistura foi aquecida a 84 oC e agitada ainda por 1 hora, depois resfriada até a temperatura ambiente, e filtrada. A torta do filtro foi secada a vácuo para dar o produto bruto, e o filtrado foi concentrado a vácuo. O resíduo foi dissolvido em DCM (20 ml). A mistura resultante foi lavada com Na2S2O3 (aq., 10 %, 10 ml), Na2CO3 (aq., 1 M, 10 ml), H2O (10 ml) e salmoura (10 ml), e extraída com DCM (10 ml x 3). Os extratos orgânicos combinados foram secados em Na2SO4 anidro, e concentrados a vácuo. O resíduo junto com o produto bruto acima foram purificados por uma cromatografia em coluna de gel de sílica cintilante (DCM/MeOH (v/v) = 95/1) para dar o composto do título como um sólido branco (293 mg, 73 %). MS (ESI, íon pos.) m/z: 471,0 [M+H]+; RMN1H (600 MHz, DMSO-d6): h 9,44 (s, 1H), 8,39 (d, J = 2,4 Hz, 2H), 7,97 (d, J = 2,4 Hz, 1H), 7,77 (s, 1H), 7,73 (d, J = 9,3 Hz, 1H), 7,61 (dd, J = 1,8, 9,3 Hz, 1H), 3,99 (s, 3H), 2,88-2,72 (m, 1H), 0,98-0,92 (m, 4H).[00238] To a solution of N-(5-(imidazo[1,2-a]pyridin-6-yl)-2-methoxy-pyridin-3-yl)cyclopropanesulfonamide (292 mg, 0.85 mmol) in acetonitrile (20 ml) was added NIS (210 mg, 0.933 mmol) at 0 °C. The mixture was heated to 84°C and stirred for a further 1 hour, then cooled to room temperature, and filtered. The filter cake was vacuum dried to give the crude product, and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (20 ml). The resulting mixture was washed with Na 2 S 2 O 3 (aq., 10%, 10 ml), Na 2 CO 3 (aq., 1 M, 10 ml), H 2 O (10 ml) and brine (10 ml), and extracted with DCM (10 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue together with the above crude product was purified by a flash silica gel column chromatography (DCM/MeOH (v/v) = 95/1) to give the title compound as a white solid (293 mg, 73% ). MS (ESI, pos. ion) m/z: 471.0 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 9.44 (s, 1H), 8.39 (d, J = 2.4 Hz, 2H), 7.97 (d, J = 2.4 Hz, 1H ), 7.77 (s, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.61 (dd, J = 1.8, 9.3 Hz, 1H), 3.99 (s, 3H), 2.88-2.72 (m, 1H), 0.98-0.92 (m, 4H).
[00239] A uma suspensão de N-(5-(3-iodoimidazo[1,2-a]piridin-6-il)- 2-metoxipiridin-3-il)ciclopropanossulfonamida (85 mg, 0,18 mmol), CuI (20,6 mg, 0,108 mmol) e Pd(PPh3)4 (41,6 mg, 0,036 mmol) em DMF (3 ml) foram adicionados trietilamina (0,05 ml, 0,36 mmol) e prop-2-in-1-ol (0,03 ml, 0,54 mmol). A mistura foi desgaseificada e carregada com argônio por 3 vezes, depois agitada na temperatura ambiente por 2,5 horas, diluída com EtOAc (10 ml), e filtrada através de um CELITE®. O filtrado foi lavado com solução aquosa de bicarbonato de sódio (20 ml) e H2O (20 ml). As camadas aquosas combinadas foram extraídas com DCM (10 ml x 3). Os extratos orgânicos combinados foram secados em Na2SO4 anidro, e concentrados a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica cintilante (DCM/MeOH (v/v) = 50/1) para dar o composto do título como um sólido amarelo (50 mg, 69 %). MS (ESI, íon pos.) m/z: 399,0 [M+H]+; RMN1H (600 MHz, DMSO-d6): h 9,45 (s, 1H), 8,66 (brs, 1H), 8,40 (d, J = 2,19 Hz, 1H), 7,95 (d, J = 2,16 Hz, 1H), 7,80 (brs, 1H), 7,68 (brs, 1H), 5,46 (t, J = 6,06 Hz, 1H), 4,48 (d, J = 4,86 Hz, 2H ), 3,99 (s, 3H), 2,83-2,74 (m, 1H), 0,97-0,91 (m, 4H). Exemplo 21 N-(5-(3-cianoimidazo[1,2-a]piridin-6-il)-2-metoxipiridin-3-il) metanossulfonamida [00239] To a suspension of N-(5-(3-iodoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)cyclopropanesulfonamide (85mg, 0.18mmol), CuI (20.6 mg, 0.108 mmol) and Pd(PPh3)4 (41.6 mg, 0.036 mmol) in DMF (3 ml) were added triethylamine (0.05 ml, 0.36 mmol) and prop-2-yn -1-ol (0.03 ml, 0.54 mmol). The mixture was degassed and charged with argon 3 times, then stirred at room temperature for 2.5 hours, diluted with EtOAc (10 ml), and filtered through a CELITE®. The filtrate was washed with aqueous sodium bicarbonate solution (20 ml) and H2O (20 ml). The combined aqueous layers were extracted with DCM (10 ml x 3). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (50 mg, 69%). MS (ESI, pos. ion) m/z: 399.0 [M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 9.45 (s, 1H), 8.66 (brs, 1H), 8.40 (d, J = 2.19 Hz, 1H), 7.95 (d , J = 2.16 Hz, 1H), 7.80 (brs, 1H), 7.68 (brs, 1H), 5.46 (t, J = 6.06 Hz, 1H), 4.48 (d , J = 4.86 Hz, 2H), 3.99 (s, 3H), 2.83-2.74 (m, 1H), 0.97-0.91 (m, 4H). Example 21 N-(5-(3-cyanoimidazo[1,2-a]pyridin-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide
[00240] A uma suspensão de 5-bromo-2-metoxipiridin-3-amina (8,16 g, 40,2 mmoles) em DCM (100 ml) foi adicionado piridina (9,71 ml, 120,6 mmoles), seguido pela adição de uma solução de cloreto de metanossulfonila (7,78 ml, 100,5 mmoles) em DCM (20 ml) às gotas na temperatura ambiente. A reação foi agitada na temperatura ambiente por 24 horas e extinta com solução HCl aquosa (1 M, 30 ml). A mistura resultante foi extraída com DCM (15 ml x 2). As fases orgânicas combinadas foram lavadas com água (50 ml x 2) e concentrada a vácuo. O resíduo foi dissolvido em metanol (50 ml), depois solução aquosa de NaOH (2 M, 50 ml) foi adicionado e a mistura agitada na temperatura ambiente por 30 minutos. O metanol foi removido sob pressão reduzida e a fase aquosa foi extraída com DCM (30 ml x 4). A fase aquosa foi depois acidificada ao pH = 2 com solução aquosa de HCl (2 M). O precipitado resultante foi coletado pela filtração para dar o composto do título como um sólido branco (6,40 g, 57 %). MS (ESI, íon pos.) m/z: 280,8 [M+H]+.To a suspension of 5-bromo-2-methoxypyridin-3-amine (8.16 g, 40.2 mmoles) in DCM (100 ml) was added pyridine (9.71 ml, 120.6 mmoles), followed by the addition of a solution of methanesulfonyl chloride (7.78 ml, 100.5 mmoles) in DCM (20 ml) dropwise at room temperature. The reaction was stirred at room temperature for 24 hours and quenched with aqueous HCl solution (1 M, 30 ml). The resulting mixture was extracted with DCM (15 ml x 2). The combined organic phases were washed with water (50 ml x 2) and concentrated in vacuo. The residue was dissolved in methanol (50 ml), then aqueous NaOH solution (2M, 50 ml) was added and the mixture stirred at room temperature for 30 minutes. Methanol was removed under reduced pressure and the aqueous phase was extracted with DCM (30 ml x 4). The aqueous phase was then acidified to pH = 2 with aqueous HCl solution (2M). The resulting precipitate was collected by filtration to give the title compound as a white solid (6.40 g, 57%). MS (ESI, pos. ion) m/z: 280.8 [M+H]+.
[00241] Uma suspensão de N-(5-bromo-2-metoxipiridin-3-il)metano- sulfonamida (3,35 g, 11,9 mmoles) e 4,4,4Ó,4Ó,5,5,5Ó,5Ó-octametil-2,2Ó- bi(1,3,2-dioxaborolano) (4,24 g, 16,7 mmoles, Beijing datianfengtuo) em tolueno (100 ml) foi desgaseificada e carregada com N2 por 3 vezes, depois Pd(dba)3 (616 mg, 0,595 mmol, Matthey) e PPh3 (243 mg, 0,892 mmol) foram adicionados. A mistura foi aquecida a 45 oC e agitada por 45 minutos, depois KOAc (3,74 g, 23,8 mmoles) foi adicionado. A mistura resultante foi aquecida ao refluxo e agitada ainda por 3 horas, depois resfriada até a temperatura ambiente, diluída com EtOAc (100 ml), e filtrada através de um CELITE®. O filtrado foi lavado com água (70 ml x 3) e salmoura (100 ml), secado em Na2SO4 anidro, e concentrado a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) = 2/1) para dar o composto do título como um sólido branco (2,90 g, 74 %). MS (ESI, íon pos.) m/z: 328,9 [M+H]+; RMN1H (600 MHz, CDCl3): h 8,32 (d, J = 1,4 Hz, 1H), 8,06 (d, J = 1,3 Hz, 1H), 6,66 (brs, 1H), 4,05 (s, 3H), 3,02 (s, 3H), 1,33 (s, 12H).[00241] A suspension of N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (3.35 g, 11.9 mmoles) and 4,4,40,40,5,5,50, 5O-octamethyl-2,2O-bi(1,3,2-dioxaborolane) (4.24 g, 16.7 mmol, Beijing datianfengtuo) in toluene (100 ml) was degassed and charged with N2 3 times, then Pd (dba)3 (616mg, 0.595mmol, Matthey) and PPh3 (243mg, 0.892mmol) were added. The mixture was heated to 45°C and stirred for 45 minutes, then KOAc (3.74 g, 23.8 mmol) was added. The resulting mixture was heated to reflux and stirred for a further 3 hours, then cooled to room temperature, diluted with EtOAc (100 ml), and filtered through a CELITE®. The filtrate was washed with water (70 ml x 3) and brine (100 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a white solid (2.90 g, 74%). MS (ESI, pos. ion) m/z: 328.9 [M+H]+; 1 H-NMR (600 MHz, CDCl3): h 8.32 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 1.3 Hz, 1H), 6.66 (brs, 1H), 4.05 (s, 3H), 3.02 (s, 3H), 1.33 (s, 12H).
[00242] Uma suspensão de 6-bromoimidazo[1,2-a]piridino-3- carbonitrila (50 mg, 0,22 mmol) em 1,4-dioxano/água (5 ml/1 ml) foi desgaseificada e carregada com N2 três vezes, depois Pd(dppf)Cl2 (37 mg, 0,045 mmol), N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2- il)piridin-3-il)metano-sulfonamida (111 mg, 0,338 mmol) e Na2CO3 (48 mg, 0,450 mmol) foram adicionados à mistura sucessivamente. A mistura foi aquecida até o refluxo e agitada ainda por 65 minutos, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi dissolvido em DCM (20 ml) e água (20 ml). A mistura resultante foi separada, e a camada aquosa foi extraída com DCM (10 ml x 2). As fases orgânicas combinadas foram lavadas com água (25 ml) e salmoura (25 ml), secadas em Na2SO4 anidro, e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 100/1) para dar o composto do título como um sólido rosa claro (35 mg, 46 %). MS (ESI, íon pos.) m/z: 344,0 [M+H]+; RMN1H (600 MHz, CDCl3): h 8,49 (s, 1H), 8,25 (brs, 1H), 8,17 (d, J = 2,28 Hz, 1H), 7,99 (d, J = 2,28 Hz, 1H), 7,86 (d, J = 8,91 Hz, 1H), 7,63 (dd, J = 1,59, 9,24 Hz, 1H), 6,86 (s, 1H), 4,10 (s, 3H), 3,07 (s, 3H). Exemplo 22 2,4-difluoro-N-(5-(3-(3-hidroxiprop-1-in-1-il)-[1,2,4]triazolo- [4,3-a]piridm-6-il)-2-metoxipiridm-3-il)benzenossulfonamida A suspension of 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile (50 mg, 0.22 mmol) in 1,4-dioxane/water (5 ml/1 ml) was degassed and charged with N2 three times, then Pd(dppf)Cl2 (37 mg, 0.045 mmol), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl)methanesulfonamide (111 mg, 0.338 mmol) and Na 2 CO 3 (48 mg, 0.450 mmol) were added to the mixture successively. The mixture was heated to reflux and stirred for a further 65 minutes, then cooled to room temperature, and concentrated in vacuo. The residue was dissolved in DCM (20 ml) and water (20 ml). The resulting mixture was separated, and the aqueous layer was extracted with DCM (10 ml x 2). The combined organic phases were washed with water (25 ml) and brine (25 ml), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 100/1) to give the title compound as a pale pink solid (35 mg, 46%). MS (ESI, pos. ion) m/z: 344.0 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 8.49 (s, 1H), 8.25 (brs, 1H), 8.17 (d, J = 2.28 Hz, 1H), 7.99 (d, J = 2.28 Hz, 1H), 7.86 (d, J = 8.91 Hz, 1H), 7.63 (dd, J = 1.59, 9.24 Hz, 1H), 6.86 (s , 1H), 4.10 (s, 3H), 3.07 (s, 3H). Example 22 2,4-difluoro-N-(5-(3-(3-hydroxyprop-1-yn-1-yl)-[1,2,4]triazolo-[4,3-a]pyridm-6- yl)-2-methoxypyridin-3-yl)benzenesulfonamide
[00243] A uma solução de 2,5-dibromopiridina (10,50 g, 44 mmoles) em 210 ml de piridina foi adicionado hidrato de hidrazina (80 %, 8,85 g, 176,4 mmoles), e a mistura foi aquecida a 110 oC e agitada ainda por 2 horas, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi diluído com DCM (1500 ml). A mistura resultante foi lavada com solução aquosa de NaOH (1 M, 350 ml), secada em Na2SO4 anidro, e concentrada a vácuo para dar o composto do título como um sólido cinza (7,87 g, 94,8 %). MS (ESI, íon pos.) m/z: 188,0[M+H]+; RMN1H (600 MHz, DMSO-d6): h 8,03 (d, J = 2,3 Hz, 1H), 7,67 (s, 1H), 7,59 (dd, J = 8,9, 2,5 Hz, 1H), 6,69 (d, J = 8,9 Hz, 1H), 4,16 (s, 2H).To a solution of 2,5-dibromopyridine (10.50 g, 44 mmoles) in 210 ml of pyridine was added hydrazine hydrate (80%, 8.85 g, 176.4 mmoles), and the mixture was heated to 110 oC and stirred for a further 2 hours, then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (1500 ml). The resulting mixture was washed with aqueous NaOH solution (1M, 350 ml), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to give the title compound as a gray solid (7.87 g, 94.8%). MS (ESI, pos. ion) m/z: 188.0[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 8.03 (d, J = 2.3 Hz, 1H), 7.67 (s, 1H), 7.59 (dd, J = 8.9, 2, 5Hz, 1H), 6.69 (d, J = 8.9Hz, 1H), 4.16 (s, 2H).
[00244] A uma mistura de 5-bromo-2-hidrazinilpiridina (7,87 g, 42 mmoles) em 200 ml de dietoximetoxietano foi adicionado o ácido p- toluenossulfônico (0,30 g, 1,7 mmol), e a mistura foi aquecida até 110 oC e agitada ainda por 20 horas, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi diluído com H2O (150 ml). A mistura resultante foi lavada com solução aquosa de NaHCO3 (saturada, 40 ml), e extraída com DCM (300 ml x 3). As fases orgânicas combinadas foram secadas em Na2SO4 anidro, e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em gel de sílica cintilante (PE/EtOAc (v/v) = 2/1) para dar o composto do título como um sólido amarelo (6,60 g, 79,77 %). MS (ESI, íon pos.) m/z: 197,9 [M+H]+; RMN1H (600 MHz, CDCl3): h 8,82 (s, 1H), 8,34 (s, 1H), 7,75 (d, J = 9,7 Hz, 1H), 7,36 (d, J = 9,7 Hz, 1H).[00244] To a mixture of 5-bromo-2-hydrazinylpyridine (7.87 g, 42 mmoles) in 200 ml of diethoxymethoxyethane was added p-toluenesulfonic acid (0.30 g, 1.7 mmol), and the mixture it was heated to 110°C and stirred for a further 20 hours, then cooled to room temperature, and concentrated in vacuo. The residue was diluted with H2O (150 ml). The resulting mixture was washed with aqueous NaHCO3 solution (saturated, 40 ml), and extracted with DCM (300 ml x 3). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a yellow solid (6.60 g, 79.77%). MS (ESI, pos. ion) m/z: 197.9 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 8.82 (s, 1H), 8.34 (s, 1H), 7.75 (d, J = 9.7 Hz, 1H), 7.36 (d, J = 9.7 Hz, 1H).
[00245] A uma mistura de 6-bromo-[1,2,4]triazolo[4,3-a]piridina (3,00 g, 15,2 mmoles) em 65 ml de 1,4-dioxano foi adicionado Pd(dppf)Cl2^CH2Cl2 (1,24 g, 1,52 mmol) e uma solução de carbonato de sódio (4,00 g, 38 mmoles) em 13 ml de água, e a mistura foi desgaseificada e carregada com N2 por 3 vezes, depois agitada na temperatura ambiente por um tempo, seguido pela adição de 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2-dioxaborolan- 2-il)piridin-3-il)benzenossulfonamida (7,78 g, 18,2 mmoles), a mistura foi desgaseificada e carregada com nitrogênio por 3 vezes, depois aquecida a 90 oC e agitada durante a noite. A mistura de reação foi resfriada até a temperatura ambiente e concentrada a vácuo. O resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 30/1) para dar o composto do título como um sólido cinza (3,00 g, 47,33 %). MS (ESI, íon pos.) m/z: 418,1 [M+H]+; RMN1H (600 MHz, CDCl3): h 10,36 (s, 1H), 9,26 (s, 1H), 8,91 (s, 1H), 8,39 (d, J = 2,3 Hz, 1H), 7,97 (d, J = 2,3 Hz, 1H), 7,88 (d, J = 9,5 Hz, 1H), 7,76 (td, J = 8,5, 6,5 Hz, 1H), 7,70 (dd, J = 9,6, 1,7 Hz, 1H), 7,61-7,54 (m, 1H), 7,24-7,15 (m, 1H), 3,64 (s, 3H).To a mixture of 6-bromo-[1,2,4]triazolo[4,3-a]pyridine (3.00 g, 15.2 mmol) in 65 ml of 1,4-dioxane was added Pd (dppf)Cl2^CH2Cl2 (1.24 g, 1.52 mmol) and a solution of sodium carbonate (4.00 g, 38 mmol) in 13 ml of water, and the mixture was degassed and charged with N2 for 3 times, then stirred at room temperature for a while, followed by the addition of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2). -yl)pyridin-3-yl)benzenesulfonamide (7.78g, 18.2mmol), the mixture was degassed and charged with nitrogen 3 times, then heated to 90°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 30/1) to give the title compound as a gray solid (3.00 g, 47.33%). MS (ESI, pos. ion) m/z: 418.1 [M+H]+; 1 H-NMR (600 MHz, CDCl 3 ): h 10.36 (s, 1H), 9.26 (s, 1H), 8.91 (s, 1H), 8.39 (d, J = 2.3 Hz, 1H ), 7.97 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.76 (td, J = 8.5, 6.5 Hz , 1H), 7.70 (dd, J = 9.6, 1.7 Hz, 1H), 7.61-7.54 (m, 1H), 7.24-7.15 (m, 1H), 3.64 (s, 3H).
[00246] A uma solução de N-(5-([1,2,4]triazolo[4,3-a]piridin-6-il)-2- metoxipiridin-3- il)-2,4-difluorobenzenossulfonamida (6,60 g, 15,83 mmoles) em CHCl3 (130 ml) foi adicionado N-bromossuccinimida (2,96 g, 16,62 mmoles) a -5 oC lentamente e agitada por 3 horas. A mistura de reação foi concentrada a vácuo e o resíduo foi purificado por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 50/1) para dar o composto do título como um sólido branco (2,80 g, 37,32 %). MS (ESI, íon pos.) m/z: 495,8 [M+H]+.[00246] To a solution of N-(5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide ( 6.60 g, 15.83 mmol) in CHCl 3 (130 ml) was added N-bromosuccinimide (2.96 g, 16.62 mmol) at -5 °C slowly and stirred for 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a white solid (2.80 g, 37.32%)). MS (ESI, pos. ion) m/z: 495.8 [M+H]+.
[00247] A uma mistura de N-(5-(3-bromo-[1,2,4]triazolo[4,3-a]piridin- 6-il)-2-metoxipiridin-3-il)-2,4-difluorobenzenossulfonamida (0,85 g, 1,79 mmol), Pd(PPh3)2Cl2 (0,126 g, 0,18 mmol) e CuI (34 mg, 0,18 mmol) em 8 ml de DMF foi adicionado trietilamina (0,904 g, 8,95 mmoles), e a mistura foi desgaseificada e carregada com nitrogênio por 3 vezes, depois prop-2-in-1-ol (0,300 g, 5,37 mmoles) foi adicionado por uma seringa. A mistura foi agitada a 50 oC sob atmosfera de N2 durante a noite, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi diluído com água (25 ml). A mistura resultante foi filtrada e a torta do filtro foi purificado ainda por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 50/1) para dar o composto do título como um sólido amarelo (0,28 g, 33,21 %). MS (ESI, íon pos.) m/z: 471,8[M+H]+; RMN1H (600 MHz, DMSO-d6): h 10,52 (s, 1H), 9,38 (s, 1H), 8,77 (s, 1H), 8,04-7,48 (m, 4H), 7,24 (t, J = 7,6 Hz, 1H), 5,47 (d, J = 5,0 Hz, 1H), 4,58-4,39 (m, 1H), 3,67 (s, 3H), 1,21 (d, J = 6,6 Hz, 3H). Exemplo 23 2,4-difluoro-N-(5-(3-(3-hidroxibut-1-in-1-il)-[1,2,4]triazolo[4,3- a]piridm-6-il)-2-metoxipiridm-3-il)benzenossulfonamida [00247] To a mixture of N-(5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2, 4-difluorobenzenesulfonamide (0.85 g, 1.79 mmol), Pd(PPh3)2Cl2 (0.126 g, 0.18 mmol) and CuI (34 mg, 0.18 mmol) in 8 ml of DMF was added triethylamine (0.904 g, 8.95 mmoles), and the mixture was degassed and charged with nitrogen 3 times, then prop-2-yn-1-ol (0.300 g, 5.37 mmoles) was added by syringe. The mixture was stirred at 50 °C under a N 2 atmosphere overnight, then cooled to room temperature, and concentrated in vacuo. The residue was diluted with water (25 ml). The resulting mixture was filtered and the filter cake was further purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.28 g, 33.21 %). MS (ESI, pos. ion) m/z: 471.8[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.52 (s, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 8.04-7.48 (m, 4H) , 7.24 (t, J = 7.6 Hz, 1H), 5.47 (d, J = 5.0 Hz, 1H), 4.58-4.39 (m, 1H), 3.67 ( s, 3H), 1.21 (d, J = 6.6 Hz, 3H). Example 23 2,4-difluoro-N-(5-(3-(3-hydroxybut-1-yn-1-yl)-[1,2,4]triazolo[4,3-a]pyridm-6-yl )-2-methoxypyridm-3-yl)benzenesulfonamide
[00248] A uma mistura de N-(5-(3-bromo-[1,2,4]triazolo[4,3-a]piridin- 6-il)-2-metoxipiridin-3-il)-2,4-difluorobenzenossulfonamida (0,85 g, 1,79 mmol), Pd(PPh3)2Cl2 (0,126 g, 0,18 mmol) e CuI (34 mg, 0,18 mmol) em 8 ml de DMF foi adicionado trietilamina (0,904 g, 8,95 mmoles), e a mistura foi desgaseificada e carregada com nitrogênio por 3 vezes, depois but-3-in-2-ol (0,376 g, 5,37 mmoles) foi adicionado por uma seringa. A mistura foi agitada a 50 oC sob atmosfera de N2 durante a noite, depois resfriada até a temperatura ambiente, e concentrada a vácuo. O resíduo foi diluído em água (25 ml). A mistura resultante foi filtrada e a torta do filtro foi purificada ainda por uma cromatografia em coluna de gel de sílica (DCM/MeOH (v/v) = 50/1) para dar o composto do título como um sólido amarelo (0,28 g, 32,25 %). MS (ESI, íon pos.) m/z: 485,9[M+H]+; RMN1H (600 MHz, DMSO-d6): h 10,52 (s, 1H), 9,38 (s, 1H), 8,77 (s, 1H), 8,04-7,48 (m, 4H), 7,24 (t, J = 7,6 Hz, 1H), 5,47 (d, J = 5,0 Hz, 1H), 4,58-4,39 (m, 1H), 3,67 (s, 3H), 1,21 (d, J = 6,6 Hz, 3H). Exemplo 24 N-(5-(3-cianoimidazo[1,2-b]piridazin-6-il)-2-metoxipiridin-3-il)- 2,4-difluorobenzenossulfonamida [00248] To a mixture of N-(5-(3-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-methoxypyridin-3-yl)-2, 4-difluorobenzenesulfonamide (0.85 g, 1.79 mmol), Pd(PPh3)2Cl2 (0.126 g, 0.18 mmol) and CuI (34 mg, 0.18 mmol) in 8 ml of DMF was added triethylamine (0.904 g, 8.95 mmoles), and the mixture was degassed and charged with nitrogen 3 times, then but-3-yn-2-ol (0.376 g, 5.37 mmoles) was added by syringe. The mixture was stirred at 50 °C under a N 2 atmosphere overnight, then cooled to room temperature, and concentrated in vacuo. The residue was diluted with water (25 ml). The resulting mixture was filtered and the filter cake was further purified by a silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as a yellow solid (0.28 g, 32.25%). MS (ESI, pos. ion) m/z: 485.9[M+H]+; 1 H-NMR (600 MHz, DMSO-d6): h 10.52 (s, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 8.04-7.48 (m, 4H) , 7.24 (t, J = 7.6 Hz, 1H), 5.47 (d, J = 5.0 Hz, 1H), 4.58-4.39 (m, 1H), 3.67 ( s, 3H), 1.21 (d, J = 6.6 Hz, 3H). Example 24 N-(5-(3-cyanoimidazo[1,2-b]pyridazin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
[00249] 2,4-difluoro-N-(2-metóxi-5-(4,4,5,5-tetrametil-1,3,2- dioxaborolan-2-il)piridin-3-il)benzenossulfonamida (1,47 g, 3,45 mmoles), 6- bromoimidazo[1,2-b]piridazina-3-carbonitrila (513 mg, 2,3 mmoles), Pd(dppf)Cl2^CH2Cl2 (188 mg, 0,23 mmol) e NébCX); (975 mg, 9,2 mmoles) foram colocados em um frasco de duas bocas, e a mistura foi desgaseificada e carregada com N2 por 3 vezes, seguido pela adição de 1,4-dioxano (50 ml) e água (10 ml). A mistura resultante foi desgaseificada e carregada com N2 por 3 vezes, depois aquecida a 90 oC e agitada ainda por 5 horas. A mistura foi depois resfriada até a temperatura ambiente, e filtrada. O filtrado foi concentrado a vácuo e o resíduo foi purificado por uma cromatografia em coluna de gel de sílica (PE/EtOAc (v/v) =2/3) para dar o composto do título como um sólido amarelo claro (580 mg, 57 %). MS (ESI, íon pos.) m/z: 443,2 [M+H]+; Pureza: 97,1 %; RMN1H (400 MHz, DMSO-d6): h 10,53 (s, 1H), 8,77 (d, J = 2,3 Hz, 1H), 8,60 (s, 1H), 8,46 (d, J = 9,6 Hz, 1H), 8,29 (d, J = 2,3 Hz, 1H), 8,17 (d, J = 9,7 Hz, 1H), 7,86-7,81 (m, 1H), 7,61-7,53 (m, 1H), 7,24 (td, J = 8,4, 2,0 Hz, 1H), 3,76 (s, 3H).[00249] 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (1 .47 g, 3.45 mmoles), 6-bromoimidazo[1,2-b]pyridazine-3-carbonitrile (513 mg, 2.3 mmoles), Pd(dppf)Cl2^CH2Cl2 (188 mg, 0.23 mmoles) ) and NebCX); (975 mg, 9.2 mmoles) were placed in a two-neck flask, and the mixture was degassed and charged with N2 3 times, followed by the addition of 1,4-dioxane (50 ml) and water (10 ml) . The resulting mixture was degassed and charged with N2 3 times, then heated to 90°C and stirred for a further 5 hours. The mixture was then cooled to room temperature, and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =2/3) to give the title compound as a pale yellow solid (580 mg, 57 %). MS (ESI, pos. ion) m/z: 443.2 [M+H]+; Purity: 97.1%; 1 H-NMR (400 MHz, DMSO-d6): h 10.53 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 8.46 (d , J = 9.6 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 9.7 Hz, 1H), 7.86-7.81 (m, 1H), 7.61-7.53 (m, 1H), 7.24 (td, J = 8.4, 2.0 Hz, 1H), 3.76 (s, 3H).
[00250] A eficácia dos compostos aqui divulgados como inibidores das PI3 cinases e mTOR cinases pode ser avaliada como segue. Os resultados de ensaio demonstram que certos compostos aqui divulgados potencialmente inibem PI3Ks e mTOR.The efficacy of the compounds disclosed herein as inhibitors of PI3 kinases and mTOR kinases can be evaluated as follows. Test results demonstrate that certain compounds disclosed herein potentially inhibit PI3Ks and mTOR.
[00251] O sistema de LC/MS/MS usado na análise consiste de um desgaseificador a vácuo Série 1200 da Agilent, bomba binária, autoamostrador de reservatório-placa, compartimento de coluna controlado com termostato, o Espectrômetro de Massa Triplo Quadripolar G6430 da Agilent com uma fonte de ionização por eletropulverização (ESI). A análise quantitativa foi realizada usando o modo MRM. Os parâmetros para as transições de MRM estão na Tabela A. Tabela A [00251] The LC/MS/MS system used in the analysis consists of an Agilent Series 1200 vacuum degasser, binary pump, reservoir-plate autosampler, thermostatically controlled column compartment, the Agilent G6430 Triple Quadripolar Mass Spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed using the MRM mode. The parameters for the MRM transitions are in Table A. Table A
[00252] Uma coluna XDB-C18 Agilent, 2,1 x 30 mm, 3,5 oM foi usada para a análise. 5 oL das amostras foram injetadas. Condição de análise: A fase móvel foi de 0,1 % de ácido fórmico em água (A) e 0,1 % de ácido fórmico em metanol (B). A taxa de fluxo foi de 0,4 ml/min. e o gradiente da Fase móvel foi como na Tabela B. Tabela B [00252] An Agilent XDB-C18 column, 2.1 x 30 mm, 3.5 oM was used for the analysis. 5 µl of the samples were injected. Analysis condition: The mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4 ml/min. and the Mobile Phase gradient was as in Table B. Table B
[00253] Alternativamente, um espectrômetro de LC/MS/MS série 6330 Agilent equipado com bombas binárias G1312A, um autoamostrador G1367A e um detector de UV G1314C foram usados na análise. Uma fonte de ESI foi usada no espectrômetro de LC/MS/MS. A análise foi feita no modo de íon positivo como apropriado e a transição de MRM para cada análito foi otimizada usando solução padrão. Uma coluna Capcell MP-C18 100 x 4,6 mm I.D., 5 oM (Phenomenex, Torrance, Califórnia, USA) foi usada durante a análise. A fase móvel foi 5 mM de acetato de amônia, 0,1 % de MeOH em água (A): 5 mM de acetato de amônia, 0,1 % de MeOH em acetonitrila (B) (70/30, v/v). A taxa de fluxo foi de 0,6 ml/min. A coluna foi mantida na temperatura ambiente. 20 oL das amostras foram injetados.[00253] Alternatively, an Agilent Series 6330 LC/MS/MS spectrometer equipped with G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis. An ESI source was used in the LC/MS/MS spectrometer. Analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution. A Capcell MP-C18 100 x 4.6 mm I.D., 5 µM column (Phenomenex, Torrance, California, USA) was used during the analysis. The mobile phase was 5 mM ammonium acetate, 0.1% MeOH in water (A): 5 mM ammonium acetate, 0.1% MeOH in acetonitrile (B) (70/30, v/v) . The flow rate was 0.6 ml/min. The column was kept at room temperature. 20 µL of the samples were injected.
[00254] As incubações de microssomas hepáticos de ser humano e rato foram conduzidas em duplicata em tubos de polipropileno. As misturas de incubação típicas consistiram de microssomas hepáticos de ser humano e rato (0,5 mg de proteína/ml), compostos de interesse (5 μM) e NADPH (1,0 mM) em um volume total de 200 μn de tampão de fosfato de potássio (PBS, 100 mM, pH = 7,4). Os compostos foram dissolvidos em DMSO e diluídos com PBS tal que a concentração final de DMSO foi de 0,05 %. As reações enzimáticas foram iniciadas com a adição de proteína depois uma pré- incubação e incubados em um banho de água aberto ao ar a 37 oC. As reações foram terminadas em vários pontos de tempo (0, 5, 10, 15, 30, 60 min) pela adição de igual volume de acetonitrila gelada. As amostras foram armazenadas a -80 oC até os ensaios de LC/MS/MS.Human and rat liver microsome incubations were conducted in duplicate in polypropylene tubes. Typical incubation mixtures consisted of human and rat liver microsomes (0.5 mg protein/ml), compounds of interest (5 µM) and NADPH (1.0 mM) in a total volume of 200 µn of buffer. potassium phosphate (PBS, 100 mM, pH = 7.4). Compounds were dissolved in DMSO and diluted with PBS such that the final concentration of DMSO was 0.05%. The enzymatic reactions were started with the addition of protein after a pre-incubation and incubated in an open air water bath at 37 oC. Reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) by the addition of an equal volume of ice-cold acetonitrile. Samples were stored at -80 oC until LC/MS/MS assays.
[00255] As concentrações de compostos nas misturas de incubação de microssomas hepáticos de ser humano e rato foram determinadas por um método de LC/MS/MS. As faixas da linearidade na faixa de concentração foram determinadas para cada um dos compostos testados.The concentrations of compounds in the human and rat liver microsome incubation mixtures were determined by an LC/MS/MS method. The linearity ranges in the concentration range were determined for each of the tested compounds.
[00256] Uma incubação paralela foi realizada usando microssomas desnaturados como o controle negativo, e as reações foram terminadas em vários pontos de tempo (0, 15, 60 min) depois da incubação a 37 oC.[00256] A parallel incubation was performed using denatured microsomes as the negative control, and reactions were terminated at various time points (0, 15, 60 min) after incubation at 37 oC.
[00257] Dextrometorfan (70 μO+ foi selecionado como o controle positive, e as reações foram terminadas em vários pontos de tempo (0, 5, 10, 15, 30, 60 min) depois da incubação a 37 oC. As amostras tanto de controle positivo quanto negativo foram incluídas em cada ensaio para garantir a integridade do sistema de incubação microssômica.[00257] Dextromethorphan (70 μO+ was selected as the positive control, and reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) after incubation at 37 oC. Both control samples positive and negative were included in each assay to ensure the integrity of the microsomal incubation system.
[00258] As concentrações de compostos nas incubações de microssoma hepático de ser humano ou rato foram plotadas como uma porcentagem do controle de ponto de tempo zero relevante para cada reação. As CLint in vivo foram extrapoladas (ref.: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29: 13161324). Tabela 2 Estabilidade de microssomas hepáticos de ser humano e rato [00258] Compound concentrations in human or rat liver microsome incubations were plotted as a percentage of the relevant zero time point control for each reaction. In vivo CLint were extrapolated (ref.: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans Drug Metabolism and Disposition 2001, 29: 13161324). Table 2 Stability of human and rat liver microsomes
[00259] Os compostos aqui divulgados são avaliados em estudos farmacocinéticos em camundongos, ratos, cães ou macacos. Os compostos são administrados como uma solução aquosa, 2 % de HPMC + 1 % de TWEEN®80 em solução aquosa, 5 % de DMSO + 5 % de solutol em solução salina, 4 % de suspensão ou cápsula de MC. Para a administração intravenosa, os animais são no geral administrados com dose de 1 ou 2 mg/kg. Para a dosagem oral (p.o.), camundongos e ratos são no geral administrados com dose de 5 ou 10 mg/kg, e cães e macacos são no geral administrados com dose de 10 mg/kg. As amostras de sangue (0,3 ml) são tiradas nos pontos de tempo de 0,25, 0,5, 1,0, 2,0, 3,0, 4,0, 6,0, 8,0, 12 e 24 h ou pontos de tempo de 0,083, 0,25, 0,5, 1,0, 2,0, 4,0, 6,0, 8,0 e 24 h e centrifugadas a 3.000 ou 4000 rpm por 2 a 10 min. As soluções plasmáticas são coletadas, armazenadas a -20 oC ou -70 oC até analisadas pela LC/MS/MS como descrito acima Tabela 3 Perfis farmacocinéticos em ratos Tabela 4 Perfis farmacocinéticos em Camundongos, Cães e Macacos[00259] The compounds disclosed herein are evaluated in pharmacokinetic studies in mice, rats, dogs or monkeys. Compounds are administered as an aqueous solution, 2% HPMC + 1% TWEEN®80 in aqueous solution, 5% DMSO + 5% solutol in saline, 4% MC suspension or capsule. For intravenous administration, animals are generally given a dose of 1 or 2 mg/kg. For oral (po) dosing, mice and rats are usually given a dose of 5 or 10 mg/kg, and dogs and monkeys are usually given a dose of 10 mg/kg. Blood samples (0.3 ml) are taken at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 h or time points of 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h and centrifuged at 3,000 or 4000 rpm for 2 to 10 min. Plasma solutions are collected, stored at -20 oC or -70 oC until analyzed by LC/MS/MS as described above Table 3 Pharmacokinetic profiles in rats Table 4 Pharmacokinetic Profiles in Mice, Dogs and Monkeys
[00260] A eficácia dos compostos aqui divulgados como inibidores das PI3 cinases e mTOR cinases pode ser avaliada como segue. Descrição Geral para Ensaios de Cinase The efficacy of the compounds disclosed herein as inhibitors of PI3 kinases and mTOR kinases can be evaluated as follows. General Description for Kinase Assays
[00261] Os ensaios de cinase podem ser realizados pela medição da incorporação de y-33P ATP em proteína básica de mielina imobilizada (MBP). Placas de 384 reservatórios brancas de alta ligação (Greiner) são revestidas com MBP (Sigma #M-1891) pela incubação de 60 μl/reservat0rio de 20 μg/ml de MBP em solução salina tamponada com Tris (TBS; 50 mM de Tris pH 8,0, 138 mM de NaCl, 2,7 mM de KCl) por 24 h a 4 oC. As placas são lavadas 3x com 100 μl de TBS. As reações de cinase são realizadas em um volume total de 34 μl em tampão de cinase (5 mM de Hepes pH 7,6, 15 mM de NaCl, 0,01 % de gama globulina bovina (Sigma #I-5506), 10 mM de MgCl2, 1 mM de DTT, 0,02 % de TritonX-100). As diluições de composto são realizadas em DMSO e adicionadas aos reservatórios de ensaio a uma concentração de DMSO final de 1 %. Cada ponto de dados é medido em duplicata, e pelo menos dois ensaios em duplicata são realizados para cada determinação de composto individual. Enzima é adicionada em concentrações finais de 10 nM ou 20 nM, por exemplo. Uma mistura de ATP não rotulado e y-33P ATP é adicionada para iniciar a reação (2 x 106 cpm de y-33P ATP por reservatório (3000 Ci/mmol) e 10 μM de ATP não rotulado, tipicamente. As reações são realizadas por 1 h na temperatura ambiente com agitação. As placas são lavadas 7x com TBS, seguido pela adição de 50 μl/reservat0rio de fluido de cintilação (Wallac). As placas são lidas usando um contador Wallac Trilux. Este é apenas um formato de tais ensaios; vários outros formatos são possíveis, como conhecido por uma pessoa de habilidade na técnica.[00261] Kinase assays can be performed by measuring the incorporation of y-33P ATP into immobilized myelin basic protein (MBP). High-binding white 384 well plates (Greiner) are coated with MBP (Sigma #M-1891) by incubating 60 µl/20 µg/ml MBP reservoir in Tris-buffered saline (TBS; 50 mM Tris pH). 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 h at 4 oC. Plates are washed 3x with 100 µl of TBS. Kinase reactions are performed in a total volume of 34 µl in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine gamma globulin (Sigma #I-5506), 10 mM MgCl 2 , 1 mM DTT, 0.02% TritonX-100). Compound dilutions are made in DMSO and added to assay wells at a final DMSO concentration of 1%. Each data point is measured in duplicate, and at least two duplicate assays are performed for each individual compound determination. Enzyme is added at final concentrations of 10 nM or 20 nM, for example. A mixture of unlabeled ATP and y-33P ATP is added to initiate the reaction (2 x 106 cpm of y-33P ATP per well (3000 Ci/mmol) and typically 10 µM of unlabeled ATP. Reactions are performed by 1 h at room temperature with shaking. Plates are washed 7x with TBS, followed by the addition of 50 µl/scintillation fluid reservoir (Wallac) Plates are read using a Wallac Trilux counter. ; several other formats are possible, as known to a person of skill in the art.
[00262] O procedimento de ensaio acima pode ser usado para determinar a IC50 para a inibição e/ou a constante de inibição, Ki. A IC50 é definida como a concentração de composto requerida para reduzir a atividade da enzima em 50 % sob a condição do ensaio. O valor de IC50 é estimado preparando-se uma curva de 10 pontos usando uma série de diluição de ^ log (por exemplo, uma curva típica pode ser preparada usando as seguintes concentrações de composto: 10 μM, 3 μM, 1 μM, 0,3 μM, 0,1 μM, 0,03 μM, 0,01 μM, 0,003 μM, 0,001 μM e 0 μM).[00262] The above test procedure can be used to determine the IC50 for inhibition and/or the inhibition constant, Ki. The IC50 is defined as the concentration of compound required to reduce enzyme activity by 50% under the test condition. The IC50 value is estimated by preparing a 10-point curve using a ^ log dilution series (for example, a typical curve can be prepared using the following compound concentrations: 10 μM, 3 μM, 1 μM, 0, 3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM and 0 μM).
[00263] PI3K (p110g/p85g) (h) é incubado em tampão de ensaio contendo 10 μM de 4,5-bisfosfato de fosfatidilinositol e MgATP (concentração como requerida). A reação é iniciada pela adição da solução de ATP. Depois da incubação por 30 minutos na temperatura ambiente, a reação é interrompida pela adição de solução de parada contendo EDTA e fosfatidilinositol-3,4,5-trisfosfato biotinilado. Finalmente, o tampão de detecção é adicionado, que contém anticorpo monoclonal anti-GST rotulado com európio, domínio GRP1 PH rotulado com GST e estreptavidina aloficocianina. A placa é depois lida no modo de fluorescência resolvida com o tempo e o sinal de fluorescência resolvido com o tempo (HTRF) é determinado de acordo com a fórmula HTRF = 10000 x (Em665nm/Em620nm).[00263] PI3K (p110g/p85g) (h) is incubated in assay buffer containing 10 µM phosphatidylinositol 4,5-bisphosphate and MgATP (concentration as required). The reaction is started by adding the ATP solution. After incubation for 30 minutes at room temperature, the reaction is stopped by the addition of a stop solution containing EDTA and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST, and allophycocyanin streptavidin. The plate is then read in the time-resolved fluorescence mode and the time-resolved fluorescence signal (HTRF) is determined according to the formula HTRF = 10000 x (Em665nm/Em620nm).
[00264] PI3K *r332β1r:7g) (h) é incubado em tampão de ensaio contendo 10 μM de fosfatidilmositol-4,5-bisfosfato e MgATP (concentração como requerida). A reação é iniciada pela adição da mistura de MgATP. Depois da incubação por 30 minutos na temperatura ambiente, a reação é interrompida pela adição de EDTA contendo solução de parada e fosfatidilinositol-3,4,5-trisfosfato biotinilado. Finalmente, o tampão de detecção é adicionado, que contém anticorpo monoclonal anti-GST rotulado com európio, domínio GRP1 PH rotulado com GST e estreptavidina- aloficocianina. A placa é depois lida no modo de fluorescência resolvida com o tempo e o sinal da fluorescência resolvida com o tempo homogênea (HTRF) é determinado de acordo com a fórmula HTRF = 10000 x (Em665nm/Em620nm).PI3K *r332β1r:7g) (h) is incubated in assay buffer containing 10 µM phosphatidylmositol-4,5-bisphosphate and MgATP (concentration as required). The reaction is started by adding the MgATP mixture. After incubation for 30 minutes at room temperature, the reaction is stopped by the addition of EDTA containing stopping solution and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST, and streptavidin-allophycocyanin. The plate is then read in the time-resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal is determined according to the formula HTRF = 10000 x (Em665nm/Em620nm).
[00265] PI3K (p110f/p85g) (h) é incubado em tampão de ensaio contendo 10 μM de fosfatidilinositol-4,5-bisfosfato e MgATP (concentração como requerida). A reação é iniciada pela adição da mistura MgATP. Depois da incubação por 30 minutos na temperatura ambiente, a reação é interrompida pela adição de EDTA contendo solução de parada e fosfatidilinositol-3,4,5-trisfosfato biotinilado. Finalmente, o tampão de detecção é adicionado, que contém anticorpo monoclonal anti-GST rotulado com európio, domínio GRP1 PH rotulado com GST e estreptavidina- aloficocianina. A placa é depois lida no modo de fluorescência resolvido com o tempo e o sinal de fluorescência resolvida com o tempo homogênea (HTRF) é determinado de acordo com a fórmula HTRF = 10000 x (Em665nm/Em620nm).[00265] PI3K (p110f/p85g) (h) is incubated in assay buffer containing 10 µM phosphatidylinositol-4,5-bisphosphate and MgATP (concentration as required). The reaction is started by adding the MgATP mixture. After incubation for 30 minutes at room temperature, the reaction is stopped by the addition of EDTA containing stopping solution and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST, and streptavidin-allophycocyanin. The plate is then read in the time-resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal is determined according to the formula HTRF = 10000 x (Em665nm/Em620nm).
[00266] PI3K (p120y + (h) é incubado em tampão de ensaio contendo 10 μM de fosfatidilinositol-4,5-bisfosfato e MgATP (concentração como requerida). A reação é iniciada pela adição da mistura de MgATP. Depois da incubação por 30 minutos na temperatura ambiente, a reação é interrompida pela adição de EDTA contendo solução de parada e fosfatidilinositol-3,4,5- trisfosfato biotinilado. Finalmente, o tampão de detecção é adicionado, que contém anticorpo monoclonal anti-GST rotulado com európio, domínio GRP1 PH rotulado com GST e estreptavidina-aloficocianina. A placa é depois lida no modo de fluorescência resolvida com o tempo e o sinal da fluorescência resolvida com o tempo homogênea (HTRF) é determinado de acordo com a fórmula HTRF = 10000 x (Em665nm/Em620nm).[00266] PI3K (p120y + (h) is incubated in assay buffer containing 10 μM phosphatidylinositol-4,5-bisphosphate and MgATP (concentration as required) The reaction is started by adding the MgATP mixture. After incubation by 30 minutes at room temperature, the reaction is stopped by the addition of EDTA containing stop solution and biotinylated phosphatidylinositol-3,4,5-trisphosphate. Finally, detection buffer is added, which contains anti-GST monoclonal antibody labeled with europium, GRP1 PH domain labeled with GST and streptavidin-allophycocyanin. The plate is then read in the time-resolved fluorescence mode and the homogeneous time-resolved fluorescence (HTRF) signal is determined according to the formula HTRF = 10000 x (Em665nm /Em620nm).
[00267] mTOR (h) é incubado com 50 mM de HEPES pH 7,5, 1 mM de EDTA, 0,01 % de Tween 20, 2 mg/ml de substrato, 3 mM de Cloreto de Manganês e ]y-33P-ATP] (atividade específica aprox. 500 cpm/pmol, concentração como requerida). A reação é iniciada pela adição da mistura de MnATP. Depois da incubação por 40 minutos na temperatura ambiente, a reação é interrompida pela adição de solução a 3 % de ácido fosfórico. 10 μn da reação são depois manchados em uma manta filtrante P30 e lavados três vezes por 5 minutos em ácido fosfórico 75 mM e uma vez em metanol antes da secagem e contagem por cintilação.[00267] mTOR (h) is incubated with 50 mM HEPES pH 7.5, 1 mM EDTA, 0.01% Tween 20, 2 mg/ml substrate, 3 mM Manganese Chloride and ]-33P -ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is started by adding the MnATP mixture. After incubation for 40 minutes at room temperature, the reaction is stopped by adding a 3% phosphoric acid solution. 10 μn of the reaction is then spotted on a P30 filter mat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and scintillation counting.
[00268] Os ensaios de cinase aqui descritos foram realizados na Millipore UK Ltd, Dundee Technology Park, Dundee DD2 1SW, UK.The kinase assays described herein were performed at Millipore UK Ltd, Dundee Technology Park, Dundee DD2 1SW, UK.
[00269] Os compostos aqui divulgados exibiram atividades potentes nos ensaios de PI3Kg*j+ e mTOR (h). A Tabela 5 listou as IC50s de alguns exemplos aqui descritos nos ensaios de PI3Kg(h) e mTOR (h). Tabela 5 Dados de inibição de cinase [00269] The compounds disclosed herein exhibited potent activities in the PI3Kg*j+ and mTOR(h) assays. Table 5 listed the IC50s of some examples described herein in the PI3Kg(h) and mTOR(h) assays. Table 5 Kinase Inhibition Data
[00270] Alternativamente, as atividades de cinase dos compostos podem ser medidas usando KINOMEscan®, que está fundamentado em um ensaio de ligação de competição que quantitativamente mede a capacidade de um composto para competir com um ligando imobilizado, direcionado ao sítio ativo. O ensaio foi realizado combinando-se três compostos: cinase rotulada com DNA; ligando imobilizado; e um composto de teste. A capacidade do composto de teste para competir com o ligando imobilizado foi medido por intermédio da PCR quantitativa do rótulo DNA.[00270] Alternatively, the kinase activities of compounds can be measured using KINOMEscan®, which is based on a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized ligand, targeting the active site. The assay was performed by combining three compounds: DNA-labeled kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand was measured by quantitative DNA tag PCR.
[00271] Para a maioria dos ensaios, as cepas de fago T7 rotuladas com cinase foram preparadas em um hospedeiro de E. coli derivado da cepa BL21. A E. coli foi cultivada até a fase log e infectada com fago T7 e incubada com agitação a 32 oC até a lise. Os lisados foram centrifugados e filtrados para remover fragmentos de célula. As cinases remanescentes foram produzidas em células HEK-293 e subsequentemente rotuladas com DNA para a detecção de qPCR. Pérolas magnéticas revestidas com estreptavidina foram tratadas com ligandos de molécula pequena biotinilada por 30 minutos na temperatura ambiente para gerar resinas de afinidade para os ensaios de cinase. As pérolas com ligando foram bloqueadas com biotina em excesso e lavadas com tampão de bloqueio (SEABLOCK® (Pierce), 1 % de BSA, 0,05 % de TWEEN®20, 1 mM de DTT) para remover ligando não ligado e para reduzir a ligação não específica. As reações de ligação foram montadas combinando-se cinases, pérolas de afinidade com ligando, e compostos de teste em 1x tampão de ligação (20 % de SEABLOCK®, 0,17x PBS, 0,05 % de TWEEN®20, 6 mM de DTT). Todas as reações foram realizadas em placas de 96 reservatórios de poliestireno em um volume final de 0,135 ml. As placas de ensaio foram incubadas na temperatura ambiente com agitação por 1 hora e as pérolas de afinidade foram lavadas com tampão de lavagem (1x PBS, 0,05 % de TWEEN®20). As pérolas foram depois recolocadas em suspensão em tampão de elução (1x PBS, 0,05 % de TWEEN®20, 0,5 μM de ligando não de afinidade biotinilada) e incubadas na temperatura ambiente com agitação por 30 minutos. A concentração de cinase nos eluídos foi medida pela qPCR.[00271] For most assays, kinase-labeled T7 phage strains were prepared in an E. coli host derived from strain BL21. E. coli was grown to log phase and infected with T7 phage and incubated with shaking at 32°C until lysis. Lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Streptavidin coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for the kinase assays. Ligand beads were blocked with excess biotin and washed with blocking buffer (SEABLOCK® (Pierce), 1% BSA, 0.05% TWEEN®20, 1 mM DTT) to remove unbound ligand and to reduce the non-specific binding. Binding reactions were set up by combining kinases, ligand affinity beads, and test compounds in 1x binding buffer (20% SEABLOCK®, 0.17x PBS, 0.05% TWEEN®20, 6mM DTT). All reactions were performed in 96-well polystyrene well plates in a final volume of 0.135 ml. Assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% TWEEN®20). The beads were then resuspended in elution buffer (1x PBS, 0.05% TWEEN®20, 0.5 µM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.
[00272] Os ensaios de cinase aqui descritos foram realizados usando KINOMEscan® Profiling Service at DiscoveRx Corporation, 42501 Albrae St. Fremont, CA 94538, USA.The kinase assays described herein were performed using KINOMEscan® Profiling Service at DiscoveRx Corporation, 42501 Albrae St. Fremont, CA 94538, USA.
[00273] A eficácia dos compostos aqui divulgados foi avaliada em um modelo de murino padrão de tumorigênese. As células de tumor humanas (células de glioblastoma U87MG da ATCC) foram expandidas em cultura, colhidas, e injetadas subcutaneamente no flanco traseiro de camundongos nus atímicos fêmeas de 6 a 7 semanas de idade (BALB/cA nu/nu, Hunan SLAC Laboratoory Animal, Co.) (n = 6 a 10 para o grupo de veículo e para cada grupo de dosagem). Quando os tumores atingiram um volume de 100 a 250 mm3, os animais foram aleatoriamente divididos em controle de veículo (por exemplo, 5 % de DMSO + 70 % de Captisol® (30 %), 7 % de HCl (pH1), 18 % de Captisol® (30 %); ou 7 % de DMSO, 7 % de HCl (pH 1), 70 % de Captisol® (30 %), 16 % de Captisol® (30 %), ou os semelhantes) e grupos de composto. A administração subsequente de composto pela gavagem oral começa em qualquer ponto do dia 0 ao dia 15 após a inoculação de célula de tumor e no geral continua com uma vez ao dia durante a duração do experimento.[00273] The efficacy of the compounds disclosed herein was evaluated in a standard murine model of tumorigenesis. Human tumor cells (ATCC U87MG glioblastoma cells) were culture-expanded, harvested, and injected subcutaneously into the hind flank of 6- to 7-week-old female athymic nude mice (BALB/cA nu/nu, Hunan SLAC Laboratory Animal , Co.) (n = 6 to 10 for the vehicle group and for each dosage group). When tumors reached a volume of 100 to 250 mm3, animals were randomly assigned to vehicle control (eg 5% DMSO + 70% Captisol® (30%), 7% HCl (pH1), 18% Captisol® (30%); or 7% DMSO, 7% HCl (pH 1), 70% Captisol® (30%), 16% Captisol® (30%), or the like) and groups of compound. Subsequent compound administration by oral gavage begins anywhere from day 0 to day 15 after tumor cell inoculation and generally continues with once daily for the duration of the experiment.
[00274] A progressão do crescimento de tumor é avaliada pelos volumes de tumor e registrada como uma função do tempo. Os eixos longo (L) e curto (W) dos tumores subcutâneos foram medidos com compassos de calibre duas vezes semanalmente, e o volume de tumor (TV) calculado como (L x W2)/2). A TGI foi calculada a partir da diferença entre os volumes de tumor médios de camundongos tratados com veículo e tratados com medicamento, expressada como uma porcentagem do volume de tumor médio do grupo de controle tratado com veículo, pela seguinte relação: [00274] Tumor growth progression is assessed by tumor volumes and recorded as a function of time. The long (L) and short (W) axes of subcutaneous tumors were measured with calipers twice weekly, and tumor volume (TV) calculated as (L x W2)/2). The TGI was calculated from the difference between the mean tumor volumes of vehicle-treated and drug-treated mice, expressed as a percentage of the mean tumor volume of the vehicle-treated control group, by the following relationship:
[00275] A análise estatística inicial é feita pela análise de medições repetidas de variação (RMANOVA), seguido pelo teste de post hoc de Scheffe para comparações múltiplas. Veículo sozinho (5 % de DMSO + 70 % de Captisol® (30 %), 7 % de HCl (pH 1), 18 % de Captisol® (30 %); ou 7 % de DMSO, 7 % de HCl (pH 1), 70 % de Captisol® (30 %), 16 % de Captisol® (30 %), ou os semelhantes) é o controle negativo. Tabela 6 Resultados selecionados de estudos de modelo de xenoenxerto de tumor (U87MG) [00275] The initial statistical analysis is done by repeated measures analysis of variation (RMANOVA), followed by Scheffe's post hoc test for multiple comparisons. Vehicle alone (5% DMSO + 70% Captisol® (30%), 7% HCl (pH 1), 18% Captisol® (30%); or 7% DMSO, 7% HCl (pH 1 ), 70% Captisol® (30%), 16% Captisol® (30%), or the like) is the negative control. Table 6 Selected results from tumor xenograft model studies (U87MG)
[00276] Finalmente, deve ser mencionado que existem caminhos alternativos de implementar a presente invenção. Consequentemente, as presentes formas de realização devem ser consideradas como ilustrativas e não restritivas e a invenção não deve ser limitada aos detalhes dados aqui, mas pode ser modificada dentro do escopo e equivalentes das reivindicações anexas. Todas as publicações e patentes aqui citadas são incorporadas por referência.[00276] Finally, it should be mentioned that there are alternative ways to implement the present invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims. All publications and patents cited herein are incorporated by reference.
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Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104496994B (en) * | 2014-01-06 | 2016-12-07 | 广东东阳光药业有限公司 | A kind of novel crystal forms of acetylenic heteroaryl compounds |
CA2952992C (en) * | 2014-06-17 | 2019-05-07 | Cisen Pharmaceutical Co., Ltd. | Pyridino[1,2-a]pyrimidone analogue used as mtor/pi3k inhibitor |
CN105503877A (en) | 2014-09-24 | 2016-04-20 | 和记黄埔医药(上海)有限公司 | Imidazopyridazine compound and application thereof |
JP6586463B2 (en) * | 2014-12-19 | 2019-10-02 | ヤンセン ファーマシューティカ エヌ.ベー. | Heterocycle-linked imidazopyridazine derivatives as PI3Kβ inhibitors |
BR112017012930A2 (en) | 2014-12-19 | 2018-01-09 | Janssen Pharmaceutica Nv | imidazopyridazine derivatives as pi3kbeta inhibitors. |
CA3025594C (en) * | 2016-06-16 | 2024-06-18 | Janssen Pharmaceutica Nv | Bicyclic pyridine, pyrazine, and pyrimidine derivatives as pi3k beta inhibitors |
US20190292179A1 (en) | 2016-07-21 | 2019-09-26 | Bristol-Myers Squibb Company | TGF Beta RECEPTOR ANTAGONISTS |
US10906905B2 (en) | 2016-10-14 | 2021-02-02 | Jiangsu Hengrui Medicine Co., Ltd. | Five-membered heteroaryl ring bridged ring derivative, preparation method therefor and medical use thereof |
CN108164525B (en) * | 2016-12-08 | 2020-09-08 | 沈阳药科大学 | Preparation method and application of anti-tumor compound |
JP7300394B2 (en) | 2017-01-17 | 2023-06-29 | ヘパリジェニックス ゲーエムベーハー | Protein kinase inhibition to promote liver regeneration or reduce or prevent hepatocyte death |
FR3064364A1 (en) * | 2017-03-27 | 2018-09-28 | S.P.C.M. Sa | METHOD OF DETERMINING CATIONIC POLYMERS |
CN118201896A (en) * | 2021-09-10 | 2024-06-14 | 传达治疗有限公司 | PI 3K-alpha inhibitors and methods of use thereof |
TW202400175A (en) * | 2022-05-10 | 2024-01-01 | 美商傳達治療有限公司 | Pi3kα inhibitors and methods of use thereof |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2036924C1 (en) * | 1989-01-31 | 1995-06-09 | Такеда Кемикал Индастриз ЛТД | Method of synthesis of imidazo-(1,2-b)-pyridazine or their salts and imidazo-(1,2-b)-pyridazine derivatives or their salts |
US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
US5716981A (en) | 1993-07-19 | 1998-02-10 | Angiogenesis Technologies, Inc. | Anti-angiogenic compositions and methods of use |
KR100392057B1 (en) | 1993-11-30 | 2003-10-30 | 맥길 유니버시티 | A Methool of Reducing Methylation of Cytosine in a Cpg Dinucleotide in a Cell |
US5578716A (en) | 1993-12-01 | 1996-11-26 | Mcgill University | DNA methyltransferase antisense oligonucleotides |
US6099562A (en) | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
US6268137B1 (en) | 1996-05-22 | 2001-07-31 | Methylgene, Inc. | Specific inhibitors of DNA methyl transferase |
AU8125098A (en) | 1997-05-30 | 1998-12-30 | Mcgill University | Dna methyltransferase genomic sequences and antisense oligonucleotides |
US6020318A (en) | 1997-05-30 | 2000-02-01 | Methylgene, Inc. | DNA methyltransferase genomic sequences and antisense oligonucleotides |
US6066625A (en) | 1998-02-03 | 2000-05-23 | Methylgene, Inc. | Optimized antisense oligonucleotides complementary to DNA methyltransferase sequences |
US6953783B1 (en) | 1998-10-19 | 2005-10-11 | Methylgene, Inc. | Modulation of gene expression by combination therapy |
EP1173562A2 (en) | 1999-05-03 | 2002-01-23 | Methylgene, Inc. | Inhibition of histone deacetylase |
CA2391952C (en) | 1999-11-23 | 2012-01-31 | Methylgene Inc. | Inhibitors of histone deacetylase |
AU2001248701A1 (en) | 2000-03-24 | 2001-10-03 | Methylgene, Inc. | Inhibitors of histone deacetylase |
WO2003006652A2 (en) | 2000-03-24 | 2003-01-23 | Methylgene, Inc. | Inhibition of specific histone deacetylase isoforms |
US6723733B2 (en) * | 2000-05-19 | 2004-04-20 | Guilford Pharmaceuticals, Inc. | Sulfonamide and carbamide derivatives of 6(5H)phenanthridinones and their uses |
US6897220B2 (en) | 2001-09-14 | 2005-05-24 | Methylgene, Inc. | Inhibitors of histone deacetylase |
US7868204B2 (en) | 2001-09-14 | 2011-01-11 | Methylgene Inc. | Inhibitors of histone deacetylase |
EP1429765A2 (en) | 2001-09-14 | 2004-06-23 | Methylgene, Inc. | Inhibitors of histone deacetylase |
US7282608B2 (en) | 2002-10-17 | 2007-10-16 | Methylgene, Inc. | Inhibitors of histone deacetylase |
CA2539117A1 (en) | 2003-09-24 | 2005-04-07 | Methylgene Inc. | Inhibitors of histone deacetylase |
JP5319113B2 (en) | 2004-03-26 | 2013-10-16 | メチルジーン インコーポレイテッド | Inhibitors of histone deacetylase |
RU2007107167A (en) | 2004-07-30 | 2008-09-10 | Метилджин, Инк. (Ca) | VEGF RECEPTOR AND HGF RECEPTOR SIGNAL INHIBITORS |
JP5200939B2 (en) | 2005-12-23 | 2013-06-05 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Bicyclic heteroaryl compounds |
RU2009107705A (en) * | 2006-08-04 | 2010-09-10 | Такеда Фармасьютикал Компани Лимитед (Jp) | CONDENSED HETEROCYCLIC COMPOUND AND ITS APPLICATION |
WO2009039140A1 (en) * | 2007-09-17 | 2009-03-26 | Smithkline Beecham Corporation | Pyridopyrimidine derivatives as pi3 kinase inhibitors |
US20100311736A1 (en) | 2007-10-22 | 2010-12-09 | Glaxosmithkline Llc | Pyridosulfonamide derivatives as p13 kinase inhibitors |
AU2008343813B2 (en) * | 2007-12-19 | 2012-04-12 | Amgen Inc. | Inhibitors of PI3 kinase |
CA2716947A1 (en) * | 2008-02-29 | 2009-09-11 | Array Biopharma Inc. | Imidazo [4,5-b] pyridine derivatives used as raf inhibitors |
AR071523A1 (en) * | 2008-04-30 | 2010-06-23 | Merck Serono Sa | FUSIONATED BICYCLE COMPOUNDS, A PROCESS FOR THEIR PREPARATION, THE COMPOSITE TO BE USED AS A MEDICINAL PRODUCT IN THE TREATMENT AND PROFILAXIS OF DISEASES, A PHARMACEUTICAL COMPOSITION AND A SET THAT INCLUDES SEPARATE PACKAGES OF THE COMPOUND AND OF AN INGREDIENT |
IN2012DN01961A (en) | 2009-08-17 | 2015-08-21 | Intellikine Llc | |
EP2571357B1 (en) * | 2010-05-21 | 2016-07-06 | Infinity Pharmaceuticals, Inc. | Chemical compounds, compositions and methods for kinase modulation |
UY33597A (en) * | 2010-09-09 | 2012-04-30 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF THE TRK |
EP2710018B8 (en) | 2011-05-19 | 2022-02-23 | Fundación del Sector Público Estatal Centro Nacional de Investigaciones Oncológicas Carlos III (F.S.P. CNIO) | Macrocyclic compounds as protein kinase inhibitors |
WO2012174312A2 (en) | 2011-06-15 | 2012-12-20 | Glaxosmithkline Llc | Benzimidazole derivatives as antiviral agents |
KR101274986B1 (en) | 2011-07-27 | 2013-06-17 | 한국과학기술원 | Imidazopyridine derivatives, PI3K and/or mTOR inhibiting composition and composition used in diseases linked to PI3K and/or mTOR comprising the same |
GB201205669D0 (en) | 2012-03-30 | 2012-05-16 | Agency Science Tech & Res | Bicyclic heterocyclic derivatives as mnk2 and mnk2 modulators and uses thereof |
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BR112015006726A2 (en) | 2017-08-22 |
US9926324B2 (en) | 2018-03-27 |
CA2889346C (en) | 2018-09-25 |
AU2013345107B2 (en) | 2016-02-25 |
SG11201502725TA (en) | 2015-05-28 |
MY180641A (en) | 2020-12-04 |
EP3299019B1 (en) | 2019-10-09 |
US20140134133A1 (en) | 2014-05-15 |
AU2013345107A1 (en) | 2015-04-30 |
JP6268183B2 (en) | 2018-01-24 |
EP2919784A4 (en) | 2016-07-06 |
EP3299019A1 (en) | 2018-03-28 |
RU2665036C9 (en) | 2018-11-12 |
ZA201502575B (en) | 2016-11-30 |
ES2661380T3 (en) | 2018-03-28 |
HK1210956A1 (en) | 2016-05-13 |
CN104755085B (en) | 2018-05-01 |
WO2014078211A1 (en) | 2014-05-22 |
KR20150083833A (en) | 2015-07-20 |
CA2889346A1 (en) | 2014-05-22 |
TWI574962B (en) | 2017-03-21 |
KR102148679B1 (en) | 2020-08-27 |
TW201422615A (en) | 2014-06-16 |
RU2665036C2 (en) | 2018-08-27 |
CN104755085A (en) | 2015-07-01 |
JP2015536994A (en) | 2015-12-24 |
RU2015116102A (en) | 2017-01-10 |
EP2919784A1 (en) | 2015-09-23 |
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